Letrozole Plus Ribociclib or Placebo as Neo-adjuvant Therapy in ER-positive, HER2-negative Early Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Letrozole Plus Ribociclib or Placebo as Neo-adjuvant Therapy in ER-positive, HER2-negative Early Breast Cancer (NCT02712723), a randomized phase 2 study. The primary outcome is Rate of PEPI Score 0 at Surgery Between Ribociclib Containing Arms (Combined) vs. Letrozole Alone Arm..

2. Clinical Question

The clinical question is about a prespecified surgical outcome, not simply whether a tumor changes during treatment. The registry describes PEPI 0 as pT stage 0, 1, or 2 at surgery, negative axillary lymph nodes, Ki67 at or below 2.7%, and ER-positive tumor status at surgery. It also states that PEPI 0 predicts a good outcome relative to a PEPI score greater than 0; that prognostic statement does not mean the trial directly measured long-term benefit through its primary endpoint.

The study description frames the comparison as asking whether adding ribociclib to letrozole increases the proportion with PEPI 0, with the goal of identifying more patients with an excellent outcome without chemotherapy. The posted primary result is a comparison of proportions at surgery. It does not, on its own, establish what happens to an individual patient or whether a treatment strategy changes longer-term outcomes.

3. Trial Design

The registry describes a randomized, parallel-group, quadruple-masked phase 2 study. Enrollment is listed as 121. The trial began in 2016-02, and primary completion is listed as 2018-08-27. Its status is active, not recruiting. The sponsor is Qamar Khan. Details of the randomization procedure, the identities of the masked parties, and the operational meaning of masking in this study are not reported in the registry record.

Three treatment groups are described: placebo plus letrozole, ribociclib 600 mg plus letrozole, and ribociclib 400 mg plus letrozole. The primary endpoint comparison combines the two ribociclib-containing groups and compares them with placebo plus letrozole. The posted primary results list 38 participants in the placebo-plus-letrozole group and 82 in the combined ribociclib groups. The combined estimate therefore represents a comparison across the two ribociclib schedules, rather than separate primary estimates for each dose group.

Letrozole was described as 2.5 mg taken orally each day in all groups. The 600 mg ribociclib group used a schedule of 21 days on and 7 days off; the 400 mg group used continuous daily dosing. The placebo description gives capsule schedules that differ according to the dosing pattern. The planned neoadjuvant treatment period for the primary endpoint was 24 weeks, with the endpoint assessed at surgery.

The registry identifies the primary endpoint as prespecified in the Statistical Analysis Plan and Study Protocol. The detailed analysis procedures, including the handling of missing endpoint data and the analysis population, are not reported in the registry record. The record lists secondary outcomes concerning cell-cycle arrest, pathological and clinical complete response, and relapse-free survival. The record does not report the detailed conduct of follow-up for the five-year relapse-free survival outcome.

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: It was pre-specified as the primary endpoint in the Statistical Analysis Plan and the Study Protocol to compare Placebo therapy (Placebo + Letrozole) and combination therapy (Ribociclib + Letrozole).

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 Rate of PEPI Score 0 at Surgery Between Ribociclib Containing Arms (Combined) vs. Letrozole Alone Arm., measured over 24 weeks.

The primary endpoint is the percentage of participants with a PEPI score of 0 at surgery after 24 weeks of neoadjuvant therapy. The registry definition combines tumor and biomarker findings: pT stage 0, 1, or 2 at surgery; negative axillary lymph nodes; Ki67 at or below 2.7%; and ER-positive tumor status at surgery. A participant must meet all of these stated features to satisfy the definition.

This endpoint is used to summarize several aspects of the tumor and lymph-node findings at surgery alongside proliferation and receptor status. The registry describes PEPI 0 as predicting a good outcome compared with a score greater than 0. That makes the endpoint relevant as a prognostic marker, but it is not itself a direct measurement of relapse-free survival or overall survival. Nor does a group-level percentage establish an individual participant’s future outcome.

The reported comparison combines the ribociclib-containing groups and contrasts them with placebo plus letrozole. The posted endpoint values are 22.0% for the combined ribociclib groups and 21.1% for placebo plus letrozole. The registry record does not report further detail about how participants with missing surgery measurements or incomplete endpoint components were classified.

7. Results Posted in the Registry

• Group B and Group C (Combined): 22.0% (18/82) versus 21.1% (8/38) on control; risk difference 0.9 percentage points (95% CI -14.9 to 16.7), risk ratio 1.04 (0.50–2.18); unadjusted two-proportion z-test p = 0.911.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Rate of Complete Cell Cycle Arrest at 2 Weeks Between Ribociclib Containing Arms (Combined) vs Letrozole Alone Arm.

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Group B and Group C (Combined): 82.9% (68/82) versus 39.5% (15/38) on control; risk difference 43.5 percentage points (95% CI 25.9 to 61.0), risk ratio 2.10 (1.40–3.15); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Group B and Group C (Combined) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes address several different stages and types of response: early cell-cycle arrest, pathological response at surgery, clinical response, and longer-term relapse-free survival. Their differences in timing and definition matter when considering the overall pattern. An early biological measurement is not interchangeable with a surgical endpoint, and neither alone answers a time-to-event question.

The registry posts numerical comparative results for complete cell-cycle arrest at Day 14 of Cycle 1. The other listed secondary outcomes—pathologic complete response, clinical complete response, and 5 Year Relapse Free Survival—do not have results reported in the registry record. The secondary evidence is therefore incomplete across the outcome set, and no overall pattern across all listed secondary endpoints can be established from the record.

The cell-cycle-arrest comparison shows a different observed pattern from the primary PEPI 0 comparison. That contrast is useful for understanding that an early biological endpoint and the later surgical endpoint need not move together. It does not establish a mechanism, explain the primary result, or show that the early endpoint predicts an individual’s outcome. The posted data do not report a formal analysis linking cell-cycle arrest to PEPI score.

In general, unadjusted secondary results carry less weight than a prespecified primary result when many outcomes or comparisons are considered. Testing multiple endpoints creates more opportunities for apparently notable results to arise by chance. Whether a multiplicity procedure was planned or applied is not reported in the registry record. The unadjusted p value should therefore be interpreted as a result for that specific secondary comparison, not as a confirmatory conclusion across the full set of outcomes.

The record does not report a comprehensive secondary-outcome analysis plan, detailed analysis populations, or results for the remaining listed outcomes. Accordingly, the secondary result can add context to the primary endpoint, but it cannot replace it or resolve the uncertainty around PEPI 0. Readers should keep the difference in endpoint, time point, and reporting completeness in view when assessing the results as a whole.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Rate of Complete Cell Cycle Arrest at 2 Weeks Between Ribociclib Containing Arms (Combined) vs Letrozole Alone Arm.
• Pathologic Complete Response Rate (pCR Rate): pCR Rate is Defined as the Proportion of Patients With no Histologic Evidence of Invasive Tumor Cells in the Surgical Breast Specimen and the Axillary Lymph Nodes
• Clinical Complete Response Rate (cCR Rate): cCR Rate is Defined as the Proportion of Patients With no Residual Tumor by Clinical Exam
• 5 Year Relapse Free Survival (RFS)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either meets the registry definition of PEPI score 0 at surgery or does not. The arm-level percentage is the proportion meeting that definition. For a binary endpoint, the number meeting the endpoint and the number assessed determine the observed percentage. The posted primary counts are 8 of 38 for placebo plus letrozole and 18 of 82 for the combined ribociclib groups.

What does a risk difference describe?

In general, a risk difference subtracts the proportion in one group from the proportion in the other. Its sign indicates which group has the larger observed proportion, according to the comparison’s ordering. A value of zero corresponds to equal observed proportions. For the primary endpoint, the posted risk difference is 0.009. This is a scale for the difference in proportions, not an odds ratio or a ratio of probabilities.

In general, a risk difference is often straightforward to interpret because it stays on the absolute-proportion scale. It can still be uncertain, especially when the amount of information is limited. The confidence interval is important alongside the point estimate because it shows a range of values consistent with the data under the interval’s assumptions. For the primary endpoint, the interval crosses zero, so it includes both directions of difference as well as no difference.

What does the p value contribute?

In general, an unadjusted p value assesses how compatible the observed data are with a specified null hypothesis, under the statistical model used. A small p value does not measure the size or clinical importance of an effect, and a large p value does not prove there is no effect. It also does not give the probability that the null hypothesis is true. The primary comparison has an unadjusted p value of 0.911. The detailed model and testing procedure used for the sponsor’s analysis are not reported in the registry record.

The cell-cycle-arrest result is also a binary comparison. Its posted percentages are 39.5% in placebo plus letrozole and 82.9% in the combined ribociclib groups, based on 15 of 38 and 68 of 82, respectively. The unadjusted p value is <0.001. The posted risk difference is 0.434, and the reported risk ratio is 2.101 with a confidence interval from 1.4 to 3.152. These are different effect measures: the risk difference represents an absolute contrast, while the risk ratio compares proportions multiplicatively. They refer to this secondary endpoint, not PEPI 0.

Why distinguish endpoints and time points?

In general, measurements taken at different times can address different questions. A cell-cycle-arrest assessment on Day 14 of Cycle 1 concerns an early biological response. PEPI 0 is determined from findings at surgery after 24 weeks of neoadjuvant therapy. A result on one endpoint cannot be substituted for a result on another, even when both are measured in the same treatment groups. Pathological response, clinical response, and relapse-free survival also represent distinct outcomes. Their results are not reported in the registry record.

Likewise, combining treatment arms changes the question being answered. The primary comparison pools the 600 mg and 400 mg ribociclib groups. It estimates the outcome for the combined ribociclib arms as posted, rather than showing the separate effect for each schedule. Whether the two schedules have similar effects, or why they were combined for this comparison, is not reported in the registry record.

What can be concluded from the reported analysis?

The registry identifies the primary endpoint as prespecified in the Statistical Analysis Plan and Study Protocol. It reports an unadjusted p value and effect estimates, but the analysis plan’s detailed modeling choices are not reported in the registry record. The record does not describe any adjustment for baseline covariates, stratification factors, or missing data in this comparison. It also lists zero posted analyses in the record-level analysis count; detailed sponsor analysis outputs beyond the reported summaries are not reported in the registry record.

In general, randomized comparisons can help distinguish treatment groups because assignment is intended to reduce systematic differences at baseline. Randomization does not eliminate uncertainty, and the result still depends on the number of participants with observed endpoint data, how outcomes are measured, and whether missing data or deviations from assigned treatment affect the analysis. The registry does not report enough detail to assess all of those features for this outcome. The posted values should therefore be read as the registry’s reported group-level summary, with the displayed precision and limitations, rather than as a full account of every analysis decision.

11. Confidence Intervals and Precision

The primary point estimate is a risk difference of 0.009. Its confidence interval extends from below zero to above zero. This means the interval includes results in which the combined ribociclib groups have a lower PEPI 0 proportion, results with no difference, and results in which they have a higher proportion. The point estimate alone gives a much narrower impression than the interval about what the trial can distinguish.

In general, a confidence interval describes uncertainty in an estimate under the assumptions of the analysis. It is not a range containing a fixed percentage of individual participant outcomes, and it does not assign probabilities to competing treatment effects. A wide interval indicates that the data do not locate the effect precisely; an interval crossing zero does not establish equivalence. The primary interval leaves substantial uncertainty about both direction and magnitude.

The observed group percentages are 21.1% for placebo plus letrozole and 22.0% for the combined ribociclib groups. Their underlying counts are 8 of 38 and 18 of 82. The numbers of observations and the frequency of the endpoint limit how finely the comparison can be estimated. The registry does not report additional precision measures for separate ribociclib-dose comparisons.

For the cell-cycle-arrest outcome, the reported risk-difference confidence interval lies above zero. Its reported risk-ratio confidence interval also lies above 1. These intervals indicate a different pattern of statistical uncertainty for that secondary measure than for the primary endpoint. They do not quantify the primary endpoint, and their interpretation is specific to cell-cycle arrest at Day 14 of Cycle 1.

Confidence intervals do not account automatically for every concern about the analysis. The registry record does not report details of missing-data handling, multiplicity adjustments, or the analysis population. Such information would help readers judge whether the posted interval and p value reflect all relevant sources of uncertainty. The reported precision should therefore be considered together with the endpoint definition, the combined-arm comparison, and the limits of the registry’s analysis detail.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total participants, and they are not observed trial group sizes. They illustrate the number of participants per arm associated with 80% or 90% power under stated planning assumptions, using the observed effect or a stated fraction of it. The scenarios are planning for 100% of the observed effect, planning for 75% of the observed effect, and planning for 50% of the observed effect.

The assumptions listed for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. For time-to-event outcomes, the planning convention gives total events; for all other outcomes, including the binary endpoints, it gives participants per arm. These illustrations use the observed effect and are not the trial’s original design assumptions, which are not reported in the registry record.

The 80% power column describes a planning target with an 80% chance of detecting the chosen effect under the assumptions, if that effect is the true one. The 90% power column represents a higher such chance under the same framework and generally requires a larger planned sample. For the primary comparison, the participant-per-arm figures rise as the planning effect is reduced: they are 32,813 and 43,926 for 100% of the observed effect; 58,113 and 77,796 for 75%; and 130,254 and 174,372 for 50%, for 80% and 90% power respectively. Smaller effects need more participants because they are harder to distinguish from random variation.

These are planning illustrations, not observed power. They do not indicate the probability that the trial’s result is correct, nor do they change the uncertainty in the observed primary estimate. They are also not a retrospective explanation of how the trial enrollment was chosen.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.211; treatment proportion p₁ = 0.220; average p̄ = 0.215.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5810 = 1.1388.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5810 = 0.4890.
4. n = (1.1388 + 0.4890)² / (0.0090)² = 32,812.3, rounded up to 32,813 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.210526315789474                          # control proportion
p1 <- 0.219512195121951                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2712723)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 32,813 (80% power), 43,926 (90% power)
 75% of observed effect: n per arm = 58,113 (80% power), 77,796 (90% power)
 50% of observed effect: n per arm = 130,254 (80% power), 174,372 (90% power)
power.prop.test: 32812.3 
Simulated power at n = 32,813 per arm: 0.800 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies PEPI score 0 at surgery as the primary endpoint and states that it was prespecified in the Statistical Analysis Plan and Study Protocol. It also lists multiple secondary outcomes, including cell-cycle arrest, pathological complete response, clinical complete response, and 5 Year Relapse Free Survival. The details of any multiplicity strategy—such as an ordered testing sequence, adjustment of significance thresholds, or designation of confirmatory secondary outcomes—are not reported in the registry record.

Multiplicity matters because repeated statistical tests increase the chance that at least one result appears unusual under a null model, even when there is no true effect on the outcomes tested. This is a general statistical concern, not evidence that any particular posted result is false. The cell-cycle-arrest p value is explicitly unadjusted, and the record does not report whether any other adjustment was applied. It should be treated as an endpoint-specific finding rather than as proof across all secondary outcomes.

Missing-data procedures are also not reported in the registry record. The primary result gives group denominators and endpoint counts, but the registry does not explain whether all randomized participants had surgery and endpoint measurements, how missing components of PEPI were handled, or whether any imputation or sensitivity analysis was used. The analysis population—such as whether participants were analyzed according to randomized assignment—is not described in the posted result details.

These omissions affect how fully a reader can assess the robustness of the estimates. If outcome availability or analysis inclusion differed between groups, the observed proportions could be affected; whether that occurred is not reported in the registry record. The record also does not report interim analyses, stopping rules, or additional details of the statistical analysis plan. Those elements should not be inferred from the posted p values or the trial’s phase designation.

The record’s statement that the endpoint was prespecified is relevant, but it does not supply all the information needed to evaluate the complete analysis process. Interpretation can rely on the reported estimates while recognizing that the missing details limit assessment of multiplicity, missingness, and analysis-population choices.

15. 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 (31.7%), alanine aminotransferase increased (14.6%), aspartate aminotransferase increased (9.8%), diarrhea (7.3%), hyperglycemia (5.4%).

Serious adverse events are reported by treatment group. The registry lists 3 affected participants among 37 at risk in the placebo-plus-letrozole group, 25 among 41 at risk in the ribociclib 600 mg-plus-letrozole group, and 20 among 41 at risk in the ribociclib 400 mg-plus-letrozole group. The deaths column lists 0, 0, and 1, respectively. These are descriptive safety counts; the record does not provide a comparative statistical analysis of these figures.

The registry also separately reports other adverse events: 19 among 37 at risk for placebo plus letrozole, 21 among 41 for ribociclib 600 mg plus letrozole, and 23 among 41 for ribociclib 400 mg plus letrozole. These figures should not be combined with the serious-event counts. The registry’s listed serious-event terms include neutrophil count decreased at 31.7%, alanine aminotransferase increased at 14.6%, aspartate aminotransferase increased at 9.8%, diarrhea at 7.3%, hyperglycemia at 5.4%, and electrocardiogram QT corrected interval prolonged at 4.9%.

The registry record does not report further detail about event severity grading, duration, attribution, or statistical comparisons. Counts alone do not establish that an event was caused by a study treatment or permit a complete comparison of safety between groups.

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

The posted primary data show PEPI score 0 in 21.1% of the placebo-plus-letrozole group and 22.0% of the combined ribociclib groups. The risk-difference estimate is 0.009, with an unadjusted p value of 0.911. The confidence interval includes both directions of difference and no difference. The result is therefore imprecise with respect to whether the combined ribociclib groups had a higher or lower underlying proportion, and it does not demonstrate equivalence.

The endpoint is a composite of surgical tumor stage, nodal status, Ki67, and ER status, and the registry describes PEPI 0 as prognostic compared with a score greater than 0. It is not a direct measure of long-term survival. The registry lists relapse-free survival as a secondary outcome, but its results are not reported in the registry record. Accordingly, the primary comparison cannot answer the longer-term question on its own.

The cell-cycle-arrest result is a secondary, early measure and has a markedly different observed pattern from the primary surgical outcome. That finding is relevant as a separate biological endpoint, but does not establish that early cell-cycle arrest causes or predicts PEPI 0, pathological response, or relapse-free survival. The registry does not report an analysis connecting these outcomes.

These data describe group outcomes in this randomized phase 2 trial and should not be generalized automatically to other populations, settings, or treatment schedules. The primary analysis pools two ribociclib doses, so it does not identify a separate estimate for either dose. The registry record also does not report sufficient detail about missing data, analysis populations, or multiplicity to resolve all methodological questions.

The result should not be read as advice for an individual patient, as evidence that a treatment works or does not work, or as a definitive answer about future outcomes. It is a statistical summary of the reported endpoints, with uncertainty and reporting limitations that remain important to its interpretation.

17. Why This Trial Matters Statistically

This trial illustrates why the endpoint and time point must be kept central when interpreting clinical research. The primary endpoint is a multidimensional status at surgery, while the reported secondary cell-cycle-arrest outcome is measured early in treatment. Their observed patterns differ. Statistical interpretation requires treating each as an answer to its own question rather than assuming that an early biological response stands in for a later surgical or long-term outcome.

It also shows why effect estimates and uncertainty should be read together. The primary risk-difference estimate is close to zero, but the interval spans values on both sides of zero. A large p value cannot prove equality, and a small p value on a secondary endpoint does not establish that the primary endpoint or longer-term outcomes differ. The distinction between evidence of a group contrast and evidence of no meaningful contrast is especially important when the estimate is imprecise.

The combination of the 600 mg and 400 mg ribociclib groups is another important design feature for interpretation. A combined estimate can address the posted comparison as defined, but cannot show the separate result for each schedule. The registry gives distinct dosing descriptions while presenting the primary result for the pooled ribociclib groups.

Finally, the record highlights the value of complete reporting. The primary endpoint is identified as prespecified, yet details about missing data, analysis populations, multiplicity, and the trial’s original sample-size assumptions are not reported in the registry record. Those details help readers judge whether statistical uncertainty and the full analysis process are adequately represented. Recognizing these limits is part of interpreting a trial result, not a reason to replace the reported data with assumptions.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary endpoint comparison combines the ribociclib 600 mg and 400 mg groups. Separate primary results by dose are not reported in the registry record, so the pooled estimate cannot establish whether the schedules produced similar or different outcomes. The treatment descriptions also specify different ribociclib schedules, which should be kept in mind when interpreting the combined result.

The primary outcome is assessed at surgery after 24 weeks, and depends on several tumor and lymph-node features. The registry does not report how participants without surgery measurements, or with missing components needed to classify PEPI, were handled. It also does not describe the analysis population or any sensitivity analyses. These gaps limit assessment of possible effects of missing information on the percentages.

The primary risk-difference interval includes both negative and positive values. The resulting uncertainty means the posted estimate does not precisely determine the direction or size of an underlying difference. The trial is identified as phase 2, and the enrollment entry is 121; the registry does not report the original sample-size assumptions or justification. Planning illustrations based on the observed effect are not a substitute for that original design information.

Only the cell-cycle-arrest comparison has posted numerical results among the listed secondary outcomes in the detailed results described. The registry record does not report results for pathological complete response, clinical complete response, or 5 Year Relapse Free Survival. As a result, the record does not permit a broad assessment across all intended outcomes or a comparison between early response and longer-term outcomes.

Further details on multiplicity, interim analyses, and the statistical methods used for the sponsor’s analysis are not reported in the registry record. The masking identities and procedures are also not described. These specific gaps constrain evaluation of analysis robustness and the interpretation of the reported comparisons.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Letrozole Plus Ribociclib or Placebo as Neo-adjuvant Therapy in ER-positive, HER2-negative Early Breast Cancer — NCT02712723.
• Registry record last updated 2026-03-11; status last verified 2026-02.
• Results first posted 2026-03-11.
• 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.

22. Record Summary

NCT02712723 is a randomized, parallel-group, quadruple-masked phase 2 trial of neoadjuvant letrozole with ribociclib or placebo in women with ER-positive, HER2-negative early breast cancer. Enrollment is listed as 121. The registry lists a start in 2016-02, primary completion on 2018-08-27, and status active, not recruiting.

The primary endpoint is the proportion with PEPI score 0 at surgery after 24 weeks. The comparison combines the two ribociclib groups and contrasts them with placebo plus letrozole. The posted values are 22.0% and 21.1%, respectively; the reported risk difference is 0.009 and the unadjusted p value is 0.911. The confidence interval includes values on either side of zero.

A secondary cell-cycle-arrest comparison at Day 14 of Cycle 1 reports 82.9% for the combined ribociclib groups and 39.5% for placebo plus letrozole, with an unadjusted p value of <0.001. Results for the other listed secondary clinical outcomes are not reported in the registry record. The record’s missing-data, multiplicity, and detailed analysis-population procedures are not reported.