Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib (NCT02913430), a randomized early/phase 1 study. The primary outcome is Progression-free Survival (PFS).

2. Clinical Question

3. Trial Design

This was a randomized, parallel-group pilot trial, with no masking. The registry identifies its phase as EARLY PHASE1 and reports enrollment of 7. The trial is marked completed. Its listed start date is 2018-04-24, and its primary completion date is 2022-04-12. These record details describe the study’s registration and conduct; they do not establish how randomization was generated, concealed, or implemented.

The two groups received different endocrine treatments, while both included palbociclib. One group received fulvestrant plus palbociclib and the other tamoxifen plus palbociclib. The posted group sizes are 5 and 2, respectively. Although the design is randomized, the small enrollment means that the posted group summaries are based on very few participants. Estimates from groups of this size can be sensitive to the outcome of an individual participant, and a comparison may be imprecise or not estimable.

The trial title and brief description identify ESR1 mutation testing in circulating tumor DNA as part of the study rationale. The stated objective was to assess longitudinal changes in plasma ESR1 mutation allele frequency between the treatment groups. The primary endpoint listed in the registry, however, is progression-free survival. The record lists four secondary outcomes: best overall response, 6-month clinical benefit rate, clinical benefit rate, and overall survival. Numerical findings for those secondary outcomes are not reported in the registry record.

The registry record does not report the randomization method, allocation concealment, or a protocol-level sample-size justification. It also does not report interim analyses or a detailed statistical analysis plan. Those details should not be inferred from the randomized, parallel-group designation or from the results that are posted.

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: Treated patients that were radiologically evaluable.

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 Progression-free Survival (PFS), measured over Up to 3 years and 351 days.

Progression-free survival (PFS) measures the time from randomization until disease progression or death, whichever occurs first. The registry defines progression using RECIST v1.1: progression can include a qualifying increase in the sum of target-lesion diameters, progression of non-target lesions, or appearance of new lesions. The record also specifies censoring rules for participants without an event, including censoring at the last tumor assessment and an earlier censoring time when an interval of 6 months passes without an assessment.

PFS is used in clinical trials because it captures the time participants remain alive without recorded progression. It combines two types of events, while relying on disease assessments to determine when progression has occurred. As a time-to-event endpoint, it can include participants whose follow-up ends before progression or death; their observations are censored rather than treated as if an event occurred at that point. In general, censoring makes the estimate depend on assumptions about follow-up and the timing of assessments.

The registry lists the endpoint timeframe as up to 3 years and 351 days and identifies the summary measure as the median with a 95% confidence interval. The reported median and available interval information are incomplete for a comparison between the two groups, so the endpoint does not establish a relative treatment effect in this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Progression-free survival is a time-to-event outcome. Each participant contributes follow-up from the defined starting point, randomization, until progression, death, or censoring. The registry defines an event as progression or death, whichever occurs first. In general, an event-time analysis uses both the timing of events and the follow-up available for participants who have not yet had an event. It does not treat every participant without a recorded event as if they were followed indefinitely.

The median of a time-to-event distribution is the time by which half of the estimated population has experienced the event, under the analysis approach used. It is a summary of the estimated event-time distribution, not an average and not an estimate of the treatment effect between groups. The posted median of 4.131 months pertains to the fulvestrant plus palbociclib arm. The registry does not post a median for the tamoxifen plus palbociclib arm, so the two medians cannot be compared using the available results.

The registry gives a 95% confidence interval for the primary summary, with a lower limit of 1.672 months and no upper limit reported. In general, a confidence interval expresses the statistical uncertainty associated with an estimate under a specified method and its assumptions. A missing bound leaves the interval incomplete as reported. It should not be filled in by deriving a value from the estimate, the lower limit, or the group size. The registry record does not identify the method used to estimate the median or its confidence interval.

Censoring is important because a participant may have no progression or death recorded before follow-up ends. The registry says PFS for a participant without an event is censored at the last tumor assessment. It also says that if an interval of 6 months passes without a tumor assessment, PFS is censored at the time of the earlier tumor assessment, even if progression or death is observed later. These rules define how the endpoint is handled in those circumstances. The record does not describe how many participants were censored, how often assessments occurred, or what happened to participants who were not radiologically evaluable.

In general, censoring is most straightforward to interpret when the reason for observation ending is not related to the participant’s underlying event risk, conditional on the analysis. If follow-up or assessment patterns differ in ways connected to progression, an estimate can be difficult to interpret. The registry’s endpoint description gives censoring rules, but it does not report enough follow-up detail to assess those assumptions. This is a limitation of interpretation, not evidence that the rules were applied incorrectly.

The record describes the primary result as a median with a 95% confidence interval, but lists zero analyses. It does not report a hazard ratio, a test statistic, a p-value, or a formal between-group estimate. In general, a hazard ratio compares event rates over time between groups under a time-to-event model; it is not the same quantity as a difference between medians. No such sponsor-reported comparison is available in this record, and a relative effect should not be reconstructed from the posted median alone.

The record also includes assumptions for a planning illustration: two-sided significance level 0.05, equal allocation between groups, and a normal approximation. The stated effect to detect is a fraction of the observed effect. For time-to-event outcomes, the illustration is described in terms of a total number of events; for other outcomes it is expressed as participants per arm. These are planning assumptions, not evidence that the trial enrolled enough participants or achieved a particular probability of detecting an effect. The registry does not report a protocol-level sample-size justification, and the numerical results of the two-arm PFS comparison are not estimable in the posted record. A planning illustration should therefore not be interpreted as observed power or as a substitute for the trial’s own design rationale.

General statistical interpretation also distinguishes an estimate from its precision. A point estimate gives a single summary, while uncertainty information indicates how much the estimate may vary under the analysis assumptions. With a very small group, the amount of information available for estimating an event-time distribution is limited, particularly if follow-up is incomplete or events are few. The record does not give the number of PFS events, so their contribution to the estimate cannot be assessed from the registry entry.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies PFS as the primary outcome and lists best overall response, 6-month clinical benefit rate, clinical benefit rate, and overall survival as secondary outcomes. The record counts 5 outcome measures in total, but reports zero analyses. Numerical results for the secondary outcomes are not reported in the registry record. The outcome names alone do not show whether, or how, those outcomes were analyzed.

When a study evaluates multiple outcomes or makes multiple comparisons, the chance of finding an apparently notable result by chance can increase. In general, a statistical plan may address this through a hierarchy of outcomes, adjustment procedures, or a clearly defined exploratory interpretation. The registry record does not report a multiplicity strategy, so it is not possible to determine whether such a strategy was specified or used. No adjustment should be assumed.

The registry does describe endpoint-specific censoring rules for PFS, including use of the last tumor assessment and an earlier censoring time after an interval of 6 months without assessment. It does not report the number of participants censored, missing assessment patterns, or how missing outcome information was handled for the secondary outcomes. The record also does not provide a full account of analysis populations beyond describing the primary endpoint population as treated patients who were radiologically evaluable.

These omissions limit assessment of how the analysis population relates to all randomized participants and how incomplete follow-up may have affected the estimates. The record does not report an intention-to-treat analysis, a per-protocol analysis, or a missing-data sensitivity analysis. Their use or absence cannot be inferred from the registry entry.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutrophil count decreased (40.0%), white blood cell decreased (20.0%).

The registry reports serious adverse events affecting 2 of 5 participants at risk in the fulvestrant plus palbociclib arm and 0 of 2 participants at risk in the tamoxifen plus palbociclib arm. It reports other adverse events affecting 5 of 5 and 2 of 2 participants at risk, respectively. These are counts within the posted safety groups; they should be read alongside the very small group sizes.

The listed serious adverse event terms include neutrophil count decreased at 40.0% and white blood cell decreased at 20.0%. The record does not give enough detail in these figures to establish the duration, severity grade, timing, or relationship of each event to a particular drug. A term appearing in the serious-event list is not, by itself, proof of causation.

One death is reported in each arm. The registry’s safety figures do not establish that either death was caused by treatment, and the record does not provide a causal attribution in the information. With so few participants, counts are descriptive and do not provide a stable estimate of comparative safety. They should not be interpreted as showing that one regimen has a higher or lower risk than the other.

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

The posted results establish that the registry records a median PFS of 4.131 months for the fulvestrant plus palbociclib group, with a listed lower confidence limit of 1.672 months and no reported upper limit. They do not provide a median PFS estimate for the tamoxifen plus palbociclib group. The record explicitly indicates that values for a two-arm comparison of this median time endpoint are missing or not estimable. A relative treatment effect cannot be recovered from these incomplete arm-level results.

The findings should be read in light of the enrollment of 7, with 5 participants in one group and 2 in the other. Such small groups provide limited information and make estimates vulnerable to substantial uncertainty. The absence of a comparator estimate is a reporting and estimability limitation; it should not be interpreted as a favorable or unfavorable outcome for that group.

The record’s stated interest in changes in ESR1 mutation allele frequency in plasma does not replace the posted primary endpoint. The registry lists four secondary outcomes, but numerical results for those outcomes are not reported in the registry record. There is no reported hazard ratio, p-value, or other numerical test of the treatment-group difference.

The safety counts describe events recorded among the participants at risk in each group. They do not establish that an event was caused by a study drug, and the small denominators make group-level comparisons particularly uncertain. No conclusion about comparative benefit or harm follows from these counts alone.

In general, a randomized design is intended to support comparison between assigned groups, but the ability to make a useful comparison also depends on enrollment, outcome information, follow-up, and analysis. Here, the registry record contains too little comparative PFS information to quantify a difference. The appropriate interpretation is descriptive: one arm has a posted median estimate, while a two-arm estimate is not available. The record does not establish that either treatment combination is superior, equivalent, or ineffective.

13. Why This Trial Matters Statistically

This trial is statistically informative in part because it illustrates the distinction between a randomized design and an estimable comparison. Randomization assigns participants to groups according to a study process, but it does not guarantee that a small trial will produce complete or precise outcome estimates. The registry reports enrollment of 7 and group sizes of 5 and 2. The posted primary results do not include a median PFS for both groups, so the randomized design cannot be translated into a numerical PFS contrast from this record.

It also illustrates why time-to-event results require more than a single median. Follow-up and censoring determine what information is available, and the endpoint definition specifies how progression, death, and gaps in assessment are handled. The registry gives censoring rules, but does not report event counts or the amount of follow-up. Those details matter when assessing how much information supports an estimate and how precisely it can be interpreted.

The record distinguishes a planned research question from posted outcome evidence. It describes an aim involving longitudinal plasma ESR1 mutation allele frequency, while listing PFS as the primary endpoint and several secondary outcomes. The registry does not report numerical results for the secondary outcomes or a formal analysis comparing PFS between groups. Outcome labels and study aims are not substitutes for estimates and uncertainty measures.

Finally, the planning assumptions in the record illustrate that a sample-size calculation is conditional on chosen design inputs and an assumed effect. Such a calculation is not observed power, and it does not show that the actual enrollment can answer the clinical question. The missing comparative estimate and small groups make clear why planned sample size, observed information, and reported inference must be kept distinct.

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 the small enrollment: 7 participants, with 5 listed in the fulvestrant plus palbociclib arm and 2 in the tamoxifen plus palbociclib arm. The posted primary PFS result is incomplete for a between-group comparison. One arm has a median estimate and a lower confidence limit, while no median or confidence limits are reported for the other arm. The registry record states that values for the two-arm comparison are missing or not estimable.

The registry describes the primary population as treated patients who were radiologically evaluable, but does not report a complete flow of participants from randomization to endpoint analysis. The number of PFS events, censoring counts, follow-up distribution, and assessment schedule are not reported. Although censoring rules are described, the available entry does not permit a detailed assessment of how follow-up affected the estimates.

The registry identifies secondary outcomes but gives no numerical results for them. It reports zero analyses and does not provide a statistical analysis plan, multiplicity approach, interim analysis information, or protocol-level sample-size justification. The randomization method and allocation concealment are also not reported in the registry record. These absences prevent evaluation of important design and analysis details; they do not establish that the details were absent from the trial conduct.

Safety interpretation is also constrained by the very small numbers at risk. The adverse event counts and listed serious-event terms are descriptive, and the record does not provide enough information to assess causality or comparative risk. Overall, the registry entry supports only a limited description of the posted endpoint and safety information, not a definitive comparative conclusion.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib — NCT02913430.
• Registry record last updated 2024-09-23; status last verified 2024-05.
• Results first posted 2024-09-23.
• 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

NCT02913430 is a completed randomized, unmasked, parallel-group pilot trial in metastatic breast cancer, listed as EARLY PHASE1. It enrolled 7 participants. The groups received fulvestrant plus palbociclib or tamoxifen plus palbociclib. The primary outcome was PFS, defined from randomization to progression or death, and the stated study objective also concerned longitudinal plasma ESR1 mutation allele frequency.

The registry reports a median PFS of 4.131 months in the fulvestrant plus palbociclib arm, with a lower confidence limit of 1.672 months and no upper limit reported. It does not report a median for the tamoxifen plus palbociclib arm, and a two-arm comparison is not estimable in the posted record. Four secondary outcomes are listed without numerical results. Safety information includes adverse event counts and one reported death in each group, but does not establish causality. The available information is descriptive and does not establish comparative efficacy or safety.