Breast Cancer Study of Preoperative Pembrolizumab + Radiation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Breast Cancer Study of Preoperative Pembrolizumab + Radiation (NCT03366844), a na phase 1, phase 2 study. The primary outcome is Changes in Tumor Infiltrating Lymphocyte Score (TILs).

2. Clinical Question

3. Trial Design

This is a phase 1 and phase 2 study of preoperative pembrolizumab combined with radiation therapy in people with operable breast cancer. The listed design is single-group, allocation is not applicable, and masking is none. The record lists enrollment of 66. These design details describe the registered study; they do not establish how many participants contributed data to any particular outcome.

The study arm is titled Pembrolizumab with RT Boost. The summary describes two intravenous doses of pembrolizumab, administered three weeks apart. At the time of the second dose, participants receive radiation to the tumor in the affected breast. The planned subsequent treatment can include breast-conserving surgery, radiation to the entire breast or chest wall after surgery, and chemotherapy. The summary says participants will receive surgery or begin chemotherapy approximately six weeks after the first dose.

The primary endpoint is change in tumor-infiltrating lymphocyte score at 8 weeks after trial initiation. Secondary outcomes listed in the registry include pembrolizumab-related adverse events, immune-related adverse events, invasive disease-free survival after preoperative radiation and pembrolizumab, and pathological complete response rate. The record also lists six outcome measures overall.

The study is marked active, not recruiting. The listed study start is 2017-12-22, and the primary completion date is 2025-02-06. These dates and status describe the registry record; they are not results. No randomized comparison is registered, so observed outcomes in this arm cannot by themselves establish how outcomes would differ under another treatment or no treatment.

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

Reasons for not completing this period:

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 Changes in Tumor Infiltrating Lymphocyte Score (TILs), measured over 8 weeks after trial initiation.

The primary endpoint is change in tumor-infiltrating lymphocyte score, or TIL score, assessed using Salgado criteria. The registry describes the score as a continuous measure, reported as a mean with standard deviation, and gives a timeframe of 8 weeks after trial initiation. It describes the range as 0-100 in percent and explains that an increase indicates immune system engagement.

TILs are immune cells found in tumor tissue. The registry’s rationale is that measuring stromal TILs as a continuous variable may provide biologically relevant information about the immune response. The study description says a pembrolizumab-alone lead-in followed by pembrolizumab with radiation allows serial assessment, with the aim of establishing the contribution of radiation to the immune response generated by pembrolizumab. This is the stated rationale, not evidence that the contribution was established.

The record says there is no formal recommendation at this stage for a clinically relevant TIL threshold. It emphasizes valid measurement methodology over selecting a threshold for clinical use. Thus, a change in this score is a biological endpoint, not by itself a measure of how a participant feels, functions, or survives. The registry record does not report the observed mean change, its variability, or an estimate of uncertainty. It also does not specify the exact baseline measurement or calculation used to define change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary endpoint as a continuous score and specifies that it is summarized using a mean and standard deviation. A mean describes the central value of observations on a numerical scale. A standard deviation describes how dispersed individual observations are around that mean. In general, these summaries answer different questions: the mean concerns the average score, while the standard deviation concerns variation among scores. Neither one alone indicates how precisely the mean or a change in the mean has been estimated.

The outcome is described as change in TIL score at 8 weeks after trial initiation. A change endpoint ordinarily compares measurements made at different times, but the exact baseline timing and operational calculation are not reported in the registry record. The description mentions serial assessment, including pembrolizumab alone followed by the combination with RT, but does not report the analysis that would quantify those changes. No observed scores or summary statistics are reported, so the numerical result cannot be interpreted.

In general, a confidence interval expresses the range of estimates compatible with the data under a specified statistical method and assumptions. Its width reflects precision: a narrower interval indicates greater precision than a wider interval, all else equal. A confidence interval for a mean change would help readers judge both the plausible size of the change and the uncertainty around that estimate. The registry information does not report a confidence interval for the primary endpoint. No interval can be inferred from the enrollment figure alone.

The registered design is single-group rather than randomized between treatment arms. In a single-group study, a before-and-after measurement can describe how scores differ over time in the observed group. In general, it cannot by itself separate a treatment effect from the natural course of disease, measurement variation, concurrent care, or other time-related influences. The registry’s stated rationale for serial assessment is to examine the contribution of RT after a pembrolizumab-alone lead-in. However, the specific contrast, model, and assumptions used for that examination are not reported. A sequence of treatment periods is not the same as random assignment to concurrent control groups.

The registry lists enrollment of 66, but this figure does not establish the number of participants with an evaluable TIL measurement or the number included in a primary analysis. The analysis population, exclusions, and handling of incomplete measurements are not reported in the registry record. In general, missing data can affect both the number of observations informing an estimate and the interpretation of that estimate. If participants with unavailable outcomes differ systematically from those with observed outcomes, a complete-case summary may not represent the full enrolled group. The record does not state whether complete-case analysis, imputation, or another method was used.

For adverse events, the record reports numbers at risk and numbers affected in the study arm, along with a separate list of leading serious event terms and percentages. These are descriptive safety summaries. The record does not specify event collection periods, whether recurrent events were counted, or the detailed definitions and attribution procedures used. Without those details, readers should not infer that the event counts represent unique participants across all categories, or use them to compare risk with an unobserved control group.

The record lists secondary outcomes that include adverse events, immune-related adverse events, invasive disease-free survival after preoperative radiation and pembrolizumab, and pathological complete response rate. It lists six outcome measures and one analysis. The statistical procedures for these outcomes, including any time-to-event methods, response definitions, or covariate adjustments, are not reported in the registry record. In general, methods must match the outcome type: continuous scores, binary responses, and time-to-event outcomes do not use identical summaries or models. No specific method should be attributed to this study without a reported analysis description.

The record’s planning framework describes illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it says the effect to detect is a stated fraction of the observed effect. It distinguishes participants per arm for outcomes other than time-to-event outcomes, for which the planning quantity is total events. Such illustrations are planning calculations, not observed power. The enrolled study itself is single-group, so a two-arm equal-allocation illustration is not a description of the registered design. No observed primary effect or numerical planning illustration is reported in the registry information, so none can be interpreted as an outcome of the trial.

In general, over-dispersion occurs when variability exceeds what a chosen statistical model assumes. It can make standard errors too small and uncertainty appear narrower than warranted if the model is not adapted. Whether over-dispersion is relevant depends on the outcome and model. The registry record does not report a model for the primary endpoint or secondary outcomes, so it does not establish that over-dispersion was assessed or that a particular correction was used.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("PembroRT - Cohort: TNBC", "PembroRT - Cohort: HR+")
n   <- c(34, 9)
m   <- c(-6.06, -0.11)
sp  <- c(29.85, 8.68)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  PembroRT - Cohort: TNBC  34  -6.060  29.850  -16.475  4.355
CARM  PembroRT - Cohort: HR+  9  -0.110  8.680  -6.782  6.562

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures, including the primary change in TIL score and secondary outcomes covering adverse events, immune-related adverse events, invasive disease-free survival, and pathological complete response. It lists one analysis, but does not provide a statistical analysis plan describing which hypotheses were tested, their order, or how inference across multiple outcomes was handled. No multiplicity adjustment is reported in the registry record.

In general, when several outcomes or hypotheses are tested, the chance of obtaining at least one apparently unusual result can increase. Statistical plans may address this through a prespecified primary endpoint, a testing hierarchy, adjusted thresholds, or an emphasis on estimation rather than multiple significance tests. The registry identifies a primary endpoint, but the available information does not say how secondary outcomes were treated inferentially. It is therefore not possible to determine whether reported analyses, if any, controlled family-wise error or used another approach.

The registry record does not describe missing-data rates for the primary endpoint, reasons for missing measurements, or methods used to handle missingness. It also does not specify whether the primary analysis included all enrolled participants, only those with measurements, or another defined population. These details matter because incomplete follow-up can affect both the estimate and its representativeness. No assumptions about missingness or sensitivity analyses are reported.

These omissions do not prove that multiplicity or missing data were ignored in the conduct of the study. They mean the relevant methods are not reported in the registry information available for interpretation. The primary endpoint result itself is also not reported, so its analysis population, precision, and sensitivity to missing data cannot be assessed.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: adrenal insufficiency (5.0%), hyponatremia (3.3%), colitis (1.7%), febrile neutropenia (1.7%), fever (1.7%).

The safety record concerns the Pembrolizumab With RT Boost group. It lists 60 at risk for serious adverse events and 3 affected. Separately, it lists 60 at risk for other adverse events and 49 affected. The record also lists 6 deaths. These are descriptive registry figures, not a comparison with an untreated or alternative-treatment group.

The leading serious adverse event terms are adrenal insufficiency, reported as 5.0%; hyponatremia, 3.3%; colitis, 1.7%; febrile neutropenia, 1.7%; fever, 1.7%; and hypotension, 1.7%. The registry record does not provide additional context about event timing, duration, recurrence, severity grading, or attribution to pembrolizumab or radiation. It also does not state whether the listed deaths were related to study treatment.

In general, an “at risk” count is the denominator used for the corresponding safety summary; it should not be confused with the number of events. Counts in separate event categories may not represent mutually exclusive groups of people, and the record does not describe whether participants could contribute to more than one category. The safety figures therefore describe what the registry lists but do not establish comparative risk or causation.

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

The registered study asks whether tumor-infiltrating lymphocyte scores change after preoperative pembrolizumab and a radiation boost, and frames that score as an indicator of immune system engagement. It also describes serial assessment as a way to investigate the contribution of RT following pembrolizumab alone. This is a biological question about a measured tumor feature. It is not, by itself, a direct measure of clinical benefit.

The registry record does not report the primary endpoint result. It therefore does not show the size or direction of any TIL score change, how variable the measurements were, or how precisely a change was estimated. It also does not provide the serial measurements or an analysis separating the contribution of pembrolizumab from that of radiation. No conclusion about the observed biological response can be drawn from the endpoint description alone.

The study is single-group, with no randomized comparator. Even if a change in TIL score were reported, a within-group change would not by itself show what would have happened under a different treatment strategy. The design would not support a direct randomized estimate of the combination’s effect relative to a control. The registry lists secondary clinical outcomes, including invasive disease-free survival and pathological complete response rate, but their results are not included in the information.

The safety summaries report affected participants and serious adverse event terms in the study group, as well as deaths. They do not provide a comparison group or establish that an event was caused by treatment. The absence of a comparative safety estimate limits what can be inferred about relative harms.

Thus, the record establishes the study’s question, intervention sequence, endpoint rationale, design, and some descriptive safety information. It does not establish whether the primary endpoint changed, whether any change was clinically meaningful, or whether the combination improved clinical outcomes. The registry also does not report enough statistical detail to assess the primary analysis’s precision, missing-data handling, or multiplicity procedures.

14. Why This Trial Matters Statistically

This study is statistically notable because it treats tumor-infiltrating lymphocyte score as a continuous biological measure rather than setting a clinical threshold. The registry rationale says that continuous scoring may retain biologically relevant information and that a clinically relevant threshold cannot yet be formally recommended. This makes measurement quality and interpretation of score changes central to the research question.

The treatment sequence also motivates a longitudinal question: the registry describes a pembrolizumab-alone lead-in followed by pembrolizumab with RT, with serial assessment intended to explore the contribution of radiation to immune response. Repeated measurements can help describe how a biomarker changes during treatment. But in a single-group sequence, interpretation depends on the timing and analysis of measurements, and a before-and-after pattern alone does not establish a causal contribution from one treatment component. The record does not report the specific analysis or its results.

The study illustrates the distinction between biological engagement and clinical outcomes. A change in TIL score may address a mechanism-related question, while pathological complete response and invasive disease-free survival concern different outcome domains. Evidence about one endpoint does not automatically answer questions about the others. The registry lists these secondary outcomes but does not report their results in the information.

Finally, the design places limits on comparative inference. The record lists a single group and no randomized control arm, so it cannot supply a randomized estimate comparing the combination with an alternative. Its value as a statistical case study lies in clarifying what a continuous biomarker endpoint can describe, what serial measurement can motivate, and why design and uncertainty matter when moving from a biological signal to claims about clinical effect.

15. 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 main trial-specific limitation for interpretation is the single-group design. Allocation is listed as not applicable, and masking is none. There is no randomized comparator to support a like-for-like estimate of the combination’s effect relative to another treatment. The record itself notes that the arms are not a randomized comparison and are not a like-for-like control comparison.

The primary endpoint is a continuous TIL score, but the registry record does not report its observed result, standard deviation, or uncertainty interval. Although the endpoint is described as a change at 8 weeks after trial initiation, the exact baseline timing and calculation of change are not given. The description explains the biological rationale and the intended serial assessment, but does not provide the measurements or analysis needed to evaluate that rationale.

Eligibility criteria and participant characteristics are not reported in the information. Nor are the number with evaluable primary outcome data, analysis populations, missingness, or reasons for unavailable outcomes. The enrollment figure of 66 should therefore not be taken as the denominator for every endpoint.

The safety information gives counts at risk and affected, leading serious event terms and percentages, and deaths. The registry information does not describe event collection periods, detailed definitions, recurrence, severity grading, or treatment attribution. The listed safety figures cannot establish causation or comparative risk.

Finally, the statistical analysis plan, multiplicity approach, and methods for secondary outcomes are not reported in the registry record. The study is marked active, not recruiting, and the listed primary completion date is 2025-02-06; the status and date do not substitute for reported outcome results. These limitations concern what can be evaluated from the registry information and do not imply that unreported analyses were not conducted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Breast Cancer Study of Preoperative Pembrolizumab + Radiation — NCT03366844.
• Registry record last updated 2026-04-20; status last verified 2026-04.
• Results first posted 2023-04-28.
• 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.

19. Record Summary

The registry record describes NCT03366844, a phase 1 and phase 2 study of preoperative pembrolizumab with a radiation boost in people with operable breast cancer. It lists a single-group design, no masking, and enrollment of 66. The summary describes two intravenous pembrolizumab doses three weeks apart, with RT Boost at the second dose, before surgery or chemotherapy.

The primary endpoint is change in TIL score at 8 weeks after trial initiation, reported as a mean with standard deviation. The registry explains the biological rationale but does not report the endpoint result. Listed secondary outcomes include adverse events, invasive disease-free survival, and pathological complete response.

The record is marked active, not recruiting. It lists 2017-12-22 as the study start and 2025-02-06 as the primary completion date. Safety entries include 3 affected among 60 at risk for serious adverse events, 49 affected among 60 at risk for other adverse events, and 6 deaths. No randomized comparison is registered.