Presurgical Treatment With Letrozole in Patients With Early-stage Breast Cancer.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Presurgical Treatment With Letrozole in Patients With Early-stage Breast Cancer. (NCT02010021), a non-randomized na study. The primary outcome is Change in Insulin Receptor Substrate 1 (IRS-1) / Phosphoinositide 3-kinase (PI3K) / Serine-threonine Protein Kinase (AKT) Pathway Activation.

2. Clinical Question

3. Trial Design

The registry describes a completed, non-randomized, unmasked, sequential study sponsored by Dartmouth-Hitchcock Medical Center. It lists the phase as NA and enrollment as 17. The study started in 2014-01, had primary completion on 2017-12-08, and is marked completed. The registry record does not report a random allocation procedure; instead, allocation is listed as non-randomized.

The two groups have different procedures and should not be interpreted as a randomized treatment-versus-control contrast. Participants in the no-drug group did not receive presurgical letrozole. Their diagnostic-biopsy tissue was to be treated with everolimus in the laboratory, and tumor tissue obtained at surgery was to be used to study cell-growth signaling pathways. In the letrozole-presurgical group, patients received letrozole before surgical resection; the arm description specifies 10-21 days. Their surgical tumor tissue was also studied ex vivo, with pathway findings compared with the no-intervention arm.

The primary endpoint description focuses on ex vivo mTORC1 inhibition with everolimus and activation of the IRS-1/PI3K/AKT pathway, assessed using phospho-AKT-T308 and phospho-AKT-S473. Its timeframe is recorded as baseline and surgery, approximately 30 days. The listed treatment period and endpoint timeframe are both registry descriptions; the record does not explain their relationship. Ki67 percentage is listed as a secondary outcome. The registry record does not report the detailed allocation process, a statistical analysis plan, or a sample-size justification.

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 Insulin Receptor Substrate 1 (IRS-1) / Phosphoinositide 3-kinase (PI3K) / Serine-threonine Protein Kinase (AKT) Pathway Activation, measured over baseline and surgery, approximately 30 days.

The primary endpoint is change in activation of the insulin receptor substrate 1 (IRS-1) / phosphoinositide 3-kinase (PI3K) / serine-threonine protein kinase (AKT) pathway. It is recorded as a mean and standard deviation for a measure expressed as percentage change. The endpoint description identifies phospho-AKT-T308 and phospho-AKT-S473 as the pathway markers used to assess activation in ER+/HER2- breast tumors.

The registry frames the comparison around ex vivo mTORC1 inhibition with everolimus (RAD001): pathway activation in tumors from patients who received presurgical letrozole is compared with activation in tumors from patients without presurgical therapy. This makes the endpoint a laboratory measure of pathway activity, rather than a direct measure of tumor size, symptoms, recurrence, or survival. The record also lists Ki67 score percentage as a secondary outcome and describes Ki67 as associated with tumor-cell growth.

Pathway markers are used to represent activity in a biological signaling process that the study sought to examine. A measured change can describe the marker response under the study’s laboratory and tissue-collection procedures, but it does not by itself establish a clinical effect. The registry record does not report the primary endpoint results, the observed variability, or the methods used to combine or analyze the two phospho-AKT measurements.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary measure as a continuous outcome summarized by a mean and standard deviation. A continuous measure can take values across a scale rather than being limited to categories. The mean describes the central value of the observations, while the standard deviation describes how spread out individual observations are around that mean. Neither statistic is reported for the primary endpoint in this record.

What does percentage change describe?

The endpoint is expressed as percentage change in pathway activation. In general, a change measure compares a measurement at one occasion with a measurement at another occasion, while a percentage-change scale expresses that change relative to a reference measurement. That can make within-person or within-sample changes easier to describe on a common scale, but interpretation depends on how the reference and change are defined. The registry gives baseline and surgery as the timeframe and names phospho-AKT-T308 and phospho-AKT-S473 as the markers. It does not report the exact calculation used to define the percentage change or how measurements from the markers were handled together.

Why compare pathway measurements?

The study description focuses on signaling through the IRS-1/PI3K/AKT pathway and asks how its activation relates to the laboratory intervention with everolimus in tumors from patients with and without presurgical letrozole. Ex vivo assessment means the tissue is studied outside the participant’s body. Such an endpoint can address a biological question about tissue response in the laboratory. It does not directly measure a clinical outcome, and a laboratory change should not be treated as proof of a change in tumor behavior.

How should group comparisons be read?

Random assignment, when used, helps balance measured and unmeasured characteristics across study groups on average. This study is listed as non-randomized, and the registry cautions that the arms are not a like-for-like control comparison. In general, non-randomized comparisons can be affected by differences in who enters each group, the timing or context of treatment, and other factors related to the outcome. Adjustment can sometimes address measured differences, but the registry record does not report an adjustment strategy. It would not be appropriate to assume one.

The sequential model and unmasked status are also recorded. These design labels describe features of how the study was organized; they do not reveal the detailed allocation sequence, concealment procedures, or assessment procedures. Those details are not reported in the registry record. The brief description says one group’s biopsy tissue was treated with everolimus in the laboratory, while the other group received letrozole before surgery and had tissue assessed at surgery. The record does not explain whether all laboratory procedures were identical across the groups.

What would precision statistics add?

In general, a confidence interval gives a range of values compatible with an estimate under the statistical model and indicates how precisely the estimate is determined. A p-value addresses how compatible the observed data are with a specified null model; it does not describe the size or clinical importance of an effect. Neither confidence intervals nor p-values for the primary endpoint are reported. Without the estimate and its uncertainty, the direction, magnitude, and precision of a result cannot be evaluated.

The registry’s planning illustration is described as using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation, with the target effect set as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not results from the trial. Their assumptions do not establish that these were the trial’s original design assumptions; the sample-size justification is not reported in the registry record. The record does not provide the calculated planning values in the registry record for interpretation.

Finally, the registry lists two outcome measures and zero analyses. The presence of a defined endpoint does not mean that an analysis result is posted. The statistical analysis plan, handling of multiple outcomes, missing measurements, and analysis populations are not reported in the registry record. Without those details, the planned endpoint can be explained, but the analytic choices and evidential strength of any result cannot be assessed.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures: the primary pathway-activation measure and the secondary outcome of Ki67 score percentage. It reports zero analyses. The record does not describe a multiplicity strategy, such as prioritizing tests, adjusting significance thresholds, or controlling error across multiple outcomes or markers. In general, when several outcomes or measurements are examined, the chance of at least one apparently notable result can increase; a prespecified strategy helps readers understand how such findings should be interpreted. No such strategy is reported, and no outcome results are posted.

The record does not state how missing or unusable tissue measurements were handled. It does not report the number of participants with evaluable primary-endpoint data, whether any observations were excluded, or whether any values were imputed. Enrollment is listed as 17, while the safety groups list 10 participants at risk in the no-drug group and 7 in the letrozole-presurgical group. The registry does not explain the relationship between enrollment and the outcome analysis population.

The analysis populations are not reported in the registry record. There is no description of whether analyses were intended to include all enrolled participants, only participants with paired tissue measurements, or another defined group. Interim analyses and stopping rules are also not reported. These omissions do not show that a particular method was or was not used; they mean the registry record does not document it. Because outcome analyses are not posted, readers cannot assess the effect of missing data or multiplicity on the results.

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 5% reporting threshold.

The registry reports no serious adverse events in either listed group: 0 affected among 10 at risk in the no-drug group and 0 affected among 7 at risk in the letrozole-presurgical group. It also reports 0 other adverse events among 10 at risk in the no-drug group and 0 among 7 at risk in the letrozole-presurgical group. Deaths are reported as 0 in each group. No serious adverse-event terms are listed.

These are counts recorded for the groups and should be read with their reported denominators. A zero count means that no events of that category were recorded in the listed group during the registry’s safety reporting; it does not prove that an event cannot occur or establish that the groups have identical safety profiles. The record does not provide further detail about event definitions, observation periods, severity grading for non-serious events, or completeness of safety follow-up. The counts alone also do not establish a causal relationship between treatment and events.

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

The record establishes that investigators planned a small, non-randomized study of presurgical letrozole and laboratory measures of breast-tumor signaling. Its primary question concerns ex vivo mTORC1 inhibition with everolimus and activation of the IRS-1/PI3K/AKT pathway in ER+/HER2- tumors from patients with and without presurgical therapy. Ki67 percentage is listed as a secondary outcome. The registry also records safety counts for the two groups.

What the record does not establish is the observed change in the pathway, the magnitude or precision of a group difference, or the Ki67 findings. No outcome analyses are reported. It therefore cannot support a conclusion about the direction of the measured pathway response or the size of any association. The absence of posted outcome estimates is not evidence that the measures did or did not change.

The non-randomized design limits causal interpretation. The registry explicitly warns that the arms are not a like-for-like control comparison. Any difference in measured tissue activity could be related to treatment, group composition, procedures, or other factors; the record does not document analysis methods that would separate these explanations. In addition, the endpoint is a laboratory pathway measure, so it should not be equated with a clinical benefit or an effect on patient outcomes.

The safety record reports zero serious adverse events, zero other adverse events, and zero deaths in the listed groups. These counts describe what is recorded, not proof of no risk. In combination, the posted information is useful for understanding the study’s design, intended biological question, and limited safety counts, but it does not provide an efficacy result or a complete statistical account.

13. Why This Trial Matters Statistically

This study illustrates why the endpoint, design, and reported analysis need to be considered together. A biological endpoint can be clearly defined—in this case, percentage change in IRS-1/PI3K/AKT pathway activation measured through phospho-AKT-T308 and phospho-AKT-S473—while the record still lacks the outcome estimates needed to judge what was observed. A stated question is not itself a result.

The non-randomized, sequential design also makes the comparison more difficult to interpret causally. The registry explicitly cautions that the groups are not a like-for-like control comparison. That caveat is important for statistical reasoning: a contrast between groups is not automatically an isolated treatment effect, especially when the groups differ in presurgical treatment and tissue procedures. Clear reporting of allocation, analysis methods, and participant flow would help readers assess these issues, but those details are not reported in the registry record.

The record also shows the distinction between planning assumptions and evidence from observed data. The described sample-size illustrations use a two-sided significance level of 0.05, equal allocation, a normal approximation, and a target based on a fraction of the observed effect. Such planning calculations are not observed power and do not substitute for reported estimates and uncertainty. The record does not report the original sample-size justification or the outcome analyses.

Finally, the listed adverse-event counts are useful descriptive information, but zero events in the reported groups do not establish an absence of risk. Overall, the study matters statistically as an example of how a registry can document a specific laboratory question while leaving essential information about results, precision, missing data, multiplicity, and analysis populations unreported.

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 most important limitation for interpretation is that the registry record reports no outcome analyses. Although enrollment is listed as 17 and the primary and secondary outcomes are named, no primary-endpoint estimate, standard deviation, confidence interval, p-value, or Ki67 result is reported. The magnitude and precision of any measured effect therefore cannot be assessed.

The allocation is non-randomized, and the registry notes that the arms are not a like-for-like control comparison. Differences between groups may reflect factors beyond presurgical letrozole. The registry record does not report adjustment methods or detailed participant characteristics that would help evaluate this concern. The sequential model and absence of masking are recorded, but the allocation procedures and any safeguards against measurement or selection bias are not reported.

The study is small in enrollment, which is listed as 17, and the safety groups list 10 and 7 participants at risk. The record does not explain how many participants contributed outcome measurements or whether any data were unavailable. The endpoint timeframe is recorded as baseline and surgery, approximately 30 days, while the letrozole arm description specifies treatment for 10-21 days; the record does not explain the relationship between these timings.

Other important details are not reported in the registry record, including the statistical analysis plan, multiplicity handling, analysis populations, missing-data methods, and the sample-size justification. The primary endpoint is a laboratory pathway measure rather than a clinical outcome, which limits what it can establish about patient-level effects. The safety counts are also limited to the recorded group totals, with no further event detail.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Presurgical Treatment With Letrozole in Patients With Early-stage Breast Cancer. — NCT02010021.
• Registry record last updated 2019-01-17; status last verified 2019-01.
• Results first posted 2018-12-19.
• 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, non-randomized, unmasked, sequential study sponsored by Dartmouth-Hitchcock Medical Center, with enrollment listed as 17 and phase recorded as NA. It compares a no-presurgical-drug group with a group receiving letrozole before surgical resection; the letrozole arm description specifies 10-21 days of treatment. Tissue was to be used ex vivo to study signaling pathways.

The primary endpoint is mean percentage change in IRS-1/PI3K/AKT pathway activation, assessed using phospho-AKT-T308 and phospho-AKT-S473. The stated comparison concerns ex vivo everolimus treatment in tumors from patients with and without presurgical letrozole. Ki67 score percentage is listed as a secondary outcome. The record reports zero analyses and does not report outcome estimates. Safety listings show zero serious adverse events, zero other adverse events, and zero deaths in both groups.