Randomized Phase II Study of Preoperative Letrozole (Femara) in Combination With Avastin in Hormone Receptor Positive Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Randomized Phase II Study of Preoperative Letrozole (Femara) in Combination With Avastin in Hormone Receptor Positive Breast Cancer (NCT00461773), a randomized phase 2 study. The primary outcome is Number of Patients With Objective Tumor Response.

2. Clinical Question

The trial asked whether preoperative treatment with letrozole and bevacizumab could be evaluated for objective tumor response in postmenopausal patients with hormone-sensitive breast cancer. Its randomized, parallel-group comparison included brief exposure to bevacizumab alone and brief exposure to bevacizumab with letrozole. The registry record identifies the primary outcome as the number of patients with objective tumor response, assessed over a timeframe of up to 18 weeks.

This question is specific to the treatment regimens and short preoperative period described in the registry. It is not a question about long-term outcomes. The record lists other outcomes, including breast conservation, radiographic tumor response, pathologic complete response, tumor response with biological correlates, and drug tolerability. These additional outcomes give context to the study’s interests but do not supply evidence about the primary response comparison. No response results are reported, so the registry record does not establish how either group performed on the primary outcome.

3. Trial Design

This was a phase II randomized study with a parallel-group design and no masking. Yale University is listed as the sponsor. The registry lists the study start as 2007-03 and primary completion as 2010-05, and gives the status as terminated. Enrollment is 5 participants.

The two groups were brief exposure to bevacizumab and brief exposure to bevacizumab with letrozole. Both drugs are listed as interventions. The registry does not report the allocation ratio, the method used to generate or conceal the randomization sequence, or further details of treatment duration and dosing. The phrase “brief exposure” is the extent of regimen detail in the arm descriptions. The study purpose describes preoperative treatment, and the primary outcome description places clinical assessment before definitive surgery.

Randomization is intended to assign participants to groups by chance, which can reduce systematic differences between groups at entry. In general, randomization does not guarantee that small groups will be similar in every characteristic. With enrollment of 5 participants, any group-level comparison would be based on very few observations. The registry record does not report baseline characteristics that would allow readers to assess the groups’ starting comparability.

The study was unmasked, so participants and study personnel were not blinded according to the registry entry. The record does not explain whether outcome assessors were masked or whether any outcome was assessed independently. It also does not report why the study was terminated. These omissions limit what can be concluded about the conduct and circumstances of the trial, but they do not establish that any particular design feature caused the termination.

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 patients.

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 Number of Patients With Objective Tumor Response, measured over Up to 18 weeks.

The primary outcome is the number of patients with objective tumor response. The registry describes clinical tumor assessment at baseline and every 2 weeks until week 18, before definitive surgery, and gives the outcome timeframe as up to 18 weeks. Its description refers to 14 weeks of neoadjuvant letrozole combined with bevacizumab. The registry record does not explain the relationship between that treatment-duration wording and the stated assessment timeframe.

Response categories in the description are complete response, partial response, progressive disease, and stable disease. Complete response means that the tumor is no longer visible. Partial response is described as at least a 50% decrease from baseline in the product of two perpendicular diameters, with no new lesions. Progressive disease is described as at least a 25% increase in that product or new lesions. Stable disease means that none of the complete, partial, or progressive disease criteria is met.

In general, an objective response endpoint uses defined tumor-assessment criteria to classify whether a measurable change has occurred. Such endpoints can provide a structured measure of short-term tumor response in a preoperative study. The registry record does not report the number of patients meeting the primary outcome, nor does it clarify which response categories were combined to form the primary count. The count and its comparison between groups are therefore not available from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the study as randomized, parallel-group, phase II, and unmasked. These labels describe broad features of the design, not a complete statistical analysis plan. The record does not report a primary-outcome statistical method, a planned hypothesis test, an adjustment strategy, or a model. It also reports 0 analyses. Accordingly, the methods below distinguish the design information that is recorded from general statistical interpretation; they do not imply that a particular method was used in the trial.

What does randomization contribute?

In general, randomization assigns participants to study groups by chance. Its purpose is to reduce systematic selection differences between groups, supporting a fair comparison of outcomes. Random allocation does not ensure that groups will have the same characteristics, especially when the enrolled sample is very small. The registry gives enrollment as 5 and lists 3 and 2 participants at risk in the two groups. It does not report how the random sequence was generated, whether allocation was concealed, or whether the final group counts reflect all enrolled participants.

Unmasked means the registry does not identify blinding for the study. In an unmasked study, knowledge of assigned treatment may affect care, reporting, or assessment in some settings. The registry does not say whether assessors were masked, so no conclusion about assessor masking is warranted. Nor does the record explain what procedures, if any, were used to limit measurement or reporting bias.

How should the response endpoint be understood?

The primary outcome is recorded as a count of participants with objective tumor response, while the description lays out clinical tumor categories and measurement criteria. The categories are complete response, partial response, progressive disease, and stable disease. The description specifies the assessment schedule and states that assessments occurred before definitive surgery. However, no participant-level observations, group counts, or analysis results are reported. The registry also does not state explicitly how the response categories were grouped for the primary count. Thus, the endpoint definition offers some clinical measurement detail, but it does not permit independent reconstruction of the endpoint result.

In general, binary outcomes classify each participant as having or not having an event according to a stated rule. A group can then be described by its event count and denominator. A comparison might use a difference in event proportions, a ratio, or another method, but the choice depends on the analysis plan and data structure. No such comparison or method is reported for this trial’s primary outcome. No new comparison can be calculated without the primary outcome counts.

What does precision mean for these data?

In general, a confidence interval gives a range of values compatible with the observed data under a specified statistical method and its assumptions. It conveys uncertainty around an estimate; it does not guarantee that the range contains the true value. With few participants, intervals for event outcomes are typically broad, and estimates may be sensitive to individual outcomes. No primary effect estimate or confidence interval is reported in the registry record, so the precision of a tumor-response comparison cannot be assessed.

The registry’s sample-size assumptions describe planning illustrations based on a fraction of the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. These are planning assumptions, not evidence that the study had a particular probability of detecting an effect. Sample-size illustrations are not observed power. The record does not report the trial’s own sample-size justification, and it does not provide the primary response effect needed to interpret such illustrations quantitatively.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability exceeds what a statistical model assumes. It can make uncertainty estimates too small if the model does not allow for that extra variability. Over-dispersion is especially relevant to some count-data models; it is not a finding established by the registry entries for this trial. The primary endpoint is described as a participant count, but no model, variance estimate, or analysis is reported. There is therefore no basis to say whether over-dispersion was assessed or whether it affected the trial’s results.

What can be concluded about the actual analysis?

The record does not report an interim analysis, a stopping rule, a missing-data method, or an analysis population beyond the primary outcome description’s phrase “All patients.” It does not state whether the primary analysis followed randomized assignment or used another population definition. The status is terminated, but no statistical reason or operational reason for termination is listed. These are unreported methodological details, not evidence that a particular procedure was or was not performed outside the registry entry. The available statistical interpretation is consequently descriptive: the trial was randomized and small, the primary endpoint was defined in broad terms, and primary outcome estimates are absent.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and several secondary outcomes: breast conservation, radiographic tumor response, pathologic complete response, tumor response with biological correlates, and drug tolerability. It also reports 6 outcome measures. The record does not describe how those outcomes were prioritized for statistical testing beyond identifying the primary endpoint, or whether any adjustment for multiple comparisons was planned. It does not report a multiplicity procedure, a family of hypotheses, or adjusted results. No conclusion about control of false-positive findings can be made from the listed outcomes alone.

Missing-data handling is not reported in the registry record. There is no account of participants who lacked an assessment, withdrew, or were excluded from an analysis. The primary outcome population is described as all patients, but no further operational definition is given. The registry also does not state whether outcomes were analyzed according to randomized assignment or whether any per-protocol or other population was used. Since no primary analysis is reported, it is not possible to assess how missing observations or exclusions may have affected the results.

In general, missing outcomes can complicate interpretation if the likelihood of being assessed is related to treatment or to the outcome itself. Statistical methods for handling missing data rely on assumptions, and those assumptions should be described when such methods are used. None are reported. Likewise, a count of planned outcome measures is not a count of completed analyses: the registry reports 0 analyses. No imputation method, sensitivity analysis, or multiplicity-adjusted inference is reported, and none should be inferred.

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.

Most frequent non-serious adverse event terms

The registry reports serious and other adverse-event counts separately for each group. In the bevacizumab group, 0 of 3 participants at risk had a serious adverse event, and 3 of 3 had an other adverse event. In the bevacizumab-and-letrozole group, 0 of 2 participants at risk had a serious adverse event, and 2 of 2 had an other adverse event. The registry reports 0 deaths in each group.

These are counts of participants, not measures of the number of separate events. The record does not define the “other” adverse-event category in the available description, and it lists no serious adverse event terms. It also does not provide event timing, severity grades, duration, or attribution to a study drug. The counts should therefore be read only as the reported group-level safety summaries.

In general, zero serious events among a small number of participants does not establish that serious events cannot occur; the estimate is imprecise when few participants are observed. Conversely, the other-event counts do not identify the types or clinical importance of those events. These entries are descriptive and should not be used to infer comparative safety beyond the limited counts recorded.

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

The registry establishes that this was a randomized phase II study of brief preoperative exposure to bevacizumab alone or with letrozole, with objective tumor response identified as the primary outcome. It records enrollment of 5 participants, a terminated status, and a clinical assessment period described as up to 18 weeks. It also gives safety counts for serious and other adverse events and deaths.

What it does not establish is the primary tumor-response result. There is no reported response count, group-specific response estimate, comparison, or confidence interval. The record therefore does not answer whether the groups differed in objective response, nor does it show the precision of any such difference. The absence of a reported primary analysis is not itself evidence that no responses occurred or that the treatments had a particular effect.

The safety entries are similarly limited. They show the reported numbers of participants with serious and other adverse events in each group, but they do not give event terms for serious events or explain the other-event category. The small denominators also limit how much can be inferred from the observed counts. No conclusion about general safety can be drawn from these counts alone.

The study’s terminated status is part of the registry record, but the reason is not reported. It should not be treated as proof of a particular scientific, safety, recruitment, or operational explanation. The record also does not provide a sample-size justification, a statistical analysis plan, details on missing outcomes, or a reported primary analysis. Those gaps constrain interpretation independently of the trial’s randomized design.

In general, a randomized trial can support a comparative estimate when outcomes are reported and the analysis is sufficiently specified. Here, the central efficacy estimate is unavailable in the registry entry. The defensible reading is that the record documents the study question and design, plus limited safety counts, while leaving the primary result and its uncertainty unreported.

13. Why This Trial Matters Statistically

This study illustrates a basic distinction between a trial’s design and its evidence. Randomization and a prespecified primary endpoint describe how a comparison was intended to be structured. They do not, by themselves, provide an estimate of the difference between groups. For this trial, the registry names objective tumor response as the primary outcome but reports no corresponding response analysis.

The enrollment of 5 participants is important statistically because it places a strong constraint on the precision that any group comparison could achieve. A very small study may be useful for exploratory assessment, but estimates based on few observations are unstable and do not necessarily provide a precise basis for comparative inference. The record does not report a sample-size justification, so the intended statistical role of the enrollment target cannot be assessed.

The entry also shows why outcome definitions and results must be considered together. The registry supplies clinical categories and assessment timing, but no primary response count or explicit summary of how those categories contributed to the endpoint. Without the observed outcome data, readers cannot evaluate the response pattern, uncertainty, or comparability between groups.

Finally, the record’s safety counts demonstrate the difference between descriptive reporting and a fuller safety analysis. Participant counts are available, but event terms and additional detail are not. The terminated status is also recorded without an explanation. These features make the study useful as an example of the limits of registry-based inference when key results and methodological details are not reported. The statistical lesson is not a conclusion about the treatments; it is that design labels and limited event counts cannot replace outcome estimates and transparent analysis reporting.

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 direct limitation is that the registry record does not report the primary tumor-response result. Although the endpoint is named and its assessment criteria are described, there is no count of participants with objective response, no group comparison, and no estimate of uncertainty. As a result, the principal study question cannot be evaluated from the posted results.

Enrollment was 5 participants, with 3 listed at risk in the bevacizumab group and 2 in the bevacizumab-and-letrozole group. These small numbers restrict the precision and interpretability of group-level comparisons. Baseline participant characteristics are not reported, so readers cannot assess the groups’ starting features. The registry does not provide a sample-size justification or describe how the enrollment target was chosen.

Important design and analysis details are also absent. The allocation ratio and randomization procedures are not reported, nor are treatment doses and detailed schedules. The record does not state whether outcome assessors were masked, how missing assessments were handled, or which analysis population was used. A statistical analysis plan, interim analyses, stopping rules, and the reason for termination are not reported in the registry record.

The endpoint description gives multiple response categories but does not explicitly state how they were combined into the primary count. It also refers to 14 weeks of neoadjuvant treatment and an assessment timeframe of up to 18 weeks; the relationship between these descriptions is not explained. For safety, serious adverse-event terms are not listed, and the other adverse-event category is not further defined. These omissions limit interpretation of both efficacy and safety without establishing that any particular outcome or procedure was absent from the conduct of the study.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Randomized Phase II Study of Preoperative Letrozole (Femara) in Combination With Avastin in Hormone Receptor Positive Breast Cancer — NCT00461773.
• Registry record last updated 2021-03-16; status last verified 2021-02.
• Results first posted 2021-03-16.
• 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

This registry entry describes a randomized, unmasked, parallel-group phase II study sponsored by Yale University. It enrolled 5 participants and compared brief exposure to bevacizumab with brief exposure to bevacizumab and letrozole in a preoperative setting. The study is listed as terminated. The registry gives the study start as 2007-03 and primary completion as 2010-05.

The primary outcome was the number of patients with objective tumor response, assessed clinically over a timeframe of up to 18 weeks. The registry lists 0 analyses and reports no primary response result. It lists secondary outcomes including breast conservation, radiographic response, pathologic complete response, biological correlates, and drug tolerability.

Safety entries report no serious adverse events and no deaths in either group, alongside other adverse events in all participants listed at risk. Serious adverse-event terms are not listed. The reason for termination, sample-size justification, detailed analysis plan, and missing-data methods are not reported in the registry record.