A Clinical Trial in Patients With Breast Cancer Susceptibility Gene (BRCA) Defective Tumours: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Clinical Trial in Patients With Breast Cancer Susceptibility Gene (BRCA) Defective Tumours (NCT01432145), a na phase 2 study. The primary outcome is Objective Response Rate to 6-mercaptopurine and Methotrexate (6MP/MTX) in This Patient Population..

2. Clinical Question

3. Trial Design

This was a phase II, single-group clinical trial sponsored by the University of Oxford. The registry lists the study as completed, with a start date of 2011-05 and primary completion in 2014-12. Enrollment was 74. The target population was patients with breast or ovarian cancer who had a known BRCA mutation.

Participants received 6-mercaptopurine and methotrexate. The recorded regimen was 6-mercaptopurine 55mg/m2 per day and methotrexate 15mg/m2 per week. Masking was listed as none. There was no randomized allocation or separate control group, so the design is not a comparison of treatment against another regimen or against a control condition.

The primary outcome description sets out a two-stage approach. At the first stage, the trial would stop for futility if fewer than 3/30 evaluable patients responded at 8 weeks. If 3 or more out of 30 evaluable patients responded, a further 35 patients would be recruited for the second stage. The registry states that this threshold was met. It does not report the response count that met the threshold or the final response result for the second stage.

The recorded enrollment and the stage description refer to different concepts: enrollment is the registry’s total enrollment, while the stage rule is expressed in terms of evaluable patients. The record does not explain the relationship between those figures. It also does not report detailed eligibility criteria, the timing or duration of treatment beyond the stated regimen, or reasons for all treatment discontinuations.

The registry lists EQ-5D-3L quality of life as a secondary outcome. It lists two outcome measures and zero analyses. A detailed statistical analysis plan, including methods for estimating the primary response result, is not reported in the registry record.

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.

Before assignment: No wash out or run-in periods. No enrolled participants were excluded from the study before assignment.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Evaluable patients are those patients who complete at least 4 out of 8 weeks of trial medication and are assessed for response as per RECIST v1.1 at 8 weeks. Patient who stop trial medication early due to disease progression are also fully evaluable as they have reached an end point.

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 Objective Response Rate to 6-mercaptopurine and Methotrexate (6MP/MTX) in This Patient Population., measured over 8 weeks after start of treatment.

The primary endpoint is the count of participants classified as responding at 8 weeks after treatment began. Although the endpoint title refers to objective response rate, the recorded outcome parameter is a count of participants. The registry describes the response proportion as something to be presented at the second stage, but does not report that proportion or the underlying response count.

Response was assessed radiologically using RECIST version 1.1, with computerised tomography (CT) and/or magnetic resonance imaging (MRI). The same method was to be used at baseline and follow-up. Complete response means disappearance of all target lesions. Partial response means at least a 30% decrease in the sum of diameters of target lesions. Stable disease means neither enough shrinkage to qualify as partial response nor enough increase to qualify as progressive disease. Progressive disease is classified as non-response.

Including stable disease in the stated response definition is important when interpreting the endpoint. The endpoint is not limited to complete and partial responses: it also counts stable disease. The reported measure therefore reflects the registry’s combined response category rather than a count restricted to tumour shrinkage.

The evaluable population includes patients who completed at least 4 out of 8 weeks of medication and received an assessment at 8 weeks. Patients who stopped medication early because of disease progression were also considered evaluable. The registry does not report how other patients with missing assessments were handled, nor does it give the number of evaluable patients or the primary endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design is a single-group phase II study, with no masking and no separate comparator. Allocation is listed as NA. In practical terms, the registry record describes outcomes among participants receiving the 6MP/MTX regimen, rather than a randomized contrast between groups. This distinction matters because a response count within one group is descriptive of that group; by itself, it does not estimate a difference between treatments.

The regimen is specified as 6-mercaptopurine 55mg/m2 per day with methotrexate 15mg/m2 per week. The primary endpoint is assessed 8 weeks after treatment starts. The response categories are based on RECIST version 1.1 imaging, with CT and/or MRI and the same method at baseline and follow-up.

How the response classification works

Complete response is defined as disappearance of all target lesions. Partial response requires at least a 30% decrease in the sum of target-lesion diameters. Stable disease is neither sufficient shrinkage for partial response nor sufficient increase for progressive disease. The registry’s primary response description counts all three categories—complete response, partial response, and stable disease—as response. Progressive disease is classified as non-response.

General statistical context: an endpoint must be defined before its result can be interpreted. Here, the meaning of “response” depends on the registry’s combined category, including stable disease. A reader should not silently replace that definition with a narrower one. The endpoint title uses the term objective response rate, while the recorded parameter is a participant count and the description says that a proportion would be presented. The numerical count and proportion are not reported in the registry record.

What the staged rule says

The trial description gives a first-stage futility rule: if fewer than 3/30 evaluable patients responded at 8 weeks, the trial would stop. If 3 or more out of 30 evaluable patients responded, the trial would recruit a further 35 patients for the second stage. The registry says the rule was met. This conveys that recruitment continued as planned under the stated rule, but it does not supply the response count at either stage or the final second-stage estimate.

General statistical context: a staged futility rule is a decision rule intended to permit stopping when early results fall below a prespecified threshold. The rule’s meaning depends on its stated endpoint and analysis population. The registry gives the threshold and says it was met, but does not report the full statistical design details or the final outcome. The sample-size justification and any operating characteristics of the rule are not reported in the registry record.

Who counts as evaluable

The registry defines evaluable patients as those who completed at least 4 out of 8 weeks of trial medication and were assessed for response at 8 weeks under RECIST version 1.1. Patients who stopped trial medication early because of disease progression are also considered fully evaluable, because they had reached an endpoint. This definition makes progression-related early discontinuation distinct from other incomplete follow-up.

The registry does not report the number of evaluable patients, the number excluded from the primary response analysis, or how missing response assessments for other reasons were handled. Enrollment was 74, but that figure alone does not establish the size of the endpoint analysis population. The record does not explain how enrollment relates to the evaluable counts referenced in the staged rule.

What statistical results would normally communicate

General statistical context: a participant count reports how many people fall into an outcome category. A proportion places that count in relation to the number assessed, which is why both the count and its denominator matter. A confidence interval communicates uncertainty around an estimate under a chosen statistical method. A p-value, when used, describes how incompatible data are with a specified null hypothesis under the assumptions of the test; it does not express the probability that a treatment works.

For this trial, the registry does not report the primary response count, denominator, proportion, confidence interval, or p-value. It lists zero analyses. No inferential method for the primary endpoint is reported in the registry record. There is therefore no sponsor-reported statistical estimate to explain or compare with an independent calculation.

Safety counts and percentages

The adverse-event record gives group-level counts at risk and affected. For serious adverse events, it lists 67 at risk and 33 affected. For other adverse events, it lists 67 at risk and 46 affected. The listed serious adverse event terms include neutrophil count decreased at 9.0%, abdominal pain at 7.5%, thromboembolic event at 4.5%, lung infection at 4.5%, fever at 3.0%, and vomiting at 3.0%.

General statistical context: percentages require a denominator and a clearly defined event window to be interpreted. The registry lists percentages for these terms but does not report their denominators or the detailed counting rules in the record available for this analysis. The percentages should therefore be read as registry-listed values, not as independently verified rates. The record also lists 52 deaths; the context needed to interpret that figure, including attribution, is not reported in the registry record.

Planning illustrations are not trial results

General statistical context: sample-size calculations describe what a hypothetical design might require under stated assumptions. They do not describe how many participants were observed to respond, and they are not observed power. The registry’s trial outcome cannot be recovered from a planning calculation. The trial-specific sample-size justification and statistical analysis plan are not reported in the registry record, and the posted primary result is not available for an independent recalculation.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("6-Mercaptopurine and Methotrexate (6MP/MTX)")
n      <- c(67)
events <- c(22)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  6-Mercaptopurine and Methotrexate (6MP/MTX)  67  22  32.8  21.8  45.4  22.8  44.7  22.8  44.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary response endpoint and EQ-5D-3L quality of life as a secondary outcome. It does not report a multiplicity adjustment or a testing hierarchy for the outcomes. The registry lists zero analyses, so there are no posted results from which to determine whether multiple outcomes or comparisons were formally tested. A statistical plan specifying how multiplicity was to be addressed is not reported in the registry record.

The primary analysis population is described through an evaluability rule: participants had to complete at least 4 out of 8 weeks of medication and have an 8-week RECIST assessment. Patients who stopped medication early because of disease progression were also considered fully evaluable. The registry does not report the number of participants who met these criteria or the number who contributed to the primary endpoint.

The record does not explain how missing 8-week assessments for reasons other than progression were handled. It does not report imputation, sensitivity analyses, or an intention-to-treat analysis. It is therefore not possible to determine from the registry record whether missing outcomes were excluded, classified in another way, or addressed through an additional method.

The registry gives enrollment as 74, but enrollment should not be treated as the endpoint denominator without a reported analysis population. The staged rule is expressed using evaluable patients, and the final evaluable count is not reported. The relationship between enrollment and the endpoint denominator is not reported in the registry record.

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 4% 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 (9.0%), abdominal pain (7.5%), thromboembolic event (4.5%), lung infection (4.5%), fever (3.0%).

The registry lists 67 participants at risk and 33 affected for serious adverse events in the 6MP/MTX group. For other adverse events, it lists 67 at risk and 46 affected. These are separate registry fields and should be read as recorded rather than treated as a comparison between treatment groups, since the trial had one group.

The listed serious adverse event terms are neutrophil count decreased at 9.0%, abdominal pain at 7.5%, thromboembolic event at 4.5%, lung infection at 4.5%, fever at 3.0%, and vomiting at 3.0%. The registry does not give the event counts or percentage denominators for these terms in the record available for this analysis. It also does not report enough detail to establish how recurrent events were counted or the precise observation period for each term.

The registry lists 52 deaths. The record does not report the context needed to determine the relationship of that figure to treatment exposure, study follow-up, or the adverse-event categories. It should not be interpreted as showing that the regimen caused those deaths. More generally, an adverse event occurring during a trial is not, on that basis alone, established as caused by the intervention. The registry record does not provide a causal assessment for the listed events.

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

The registry record documents a completed phase II study of 6-mercaptopurine and methotrexate in patients with breast or ovarian cancer and known BRCA mutations. It describes a single-group regimen, an 8-week response assessment, a RECIST-based classification, and a staged recruitment rule. It also reports group-level safety counts and selected serious adverse event percentages.

The record does not report the primary endpoint result. There is no response count, response proportion, or uncertainty estimate, and the registry lists zero analyses. The statement that the first-stage threshold was met indicates that the stated rule permitted recruitment of the further group. It does not provide the final response result or show how precisely any response proportion was estimated.

The trial has no separate comparator group. Consequently, the posted information cannot quantify a treatment difference or distinguish outcomes associated with the regimen from outcomes that might have occurred under another treatment or without it. The design is suitable for describing outcomes in the trial group, but the registry record does not support a comparative efficacy conclusion.

The endpoint definition also matters: stable disease is counted with complete and partial response, while progressive disease is classified as non-response. Interpretation should follow that recorded definition rather than assume that response means tumour shrinkage alone.

The adverse-event fields indicate that events were recorded in the group, but the registry does not provide all denominators and contextual details needed for a full safety interpretation. The listed deaths cannot be attributed to treatment on the basis of this record. The results describe what the registry reports; they do not establish that the regimen does or does not work, and they do not support medical decisions for an individual patient.

14. Why This Trial Matters Statistically

This trial illustrates why the outcome definition and analysis population need to be read together. The primary outcome is described as an objective response rate, but the recorded parameter is a participant count, and the response definition includes stable disease as well as complete and partial response. The evaluable population also has a specific rule, including patients who stop early because of disease progression. These details determine what an eventual estimate would represent.

The staged rule is another important statistical feature. The registry specifies a futility threshold for the first stage and says that the threshold was met, but does not post the response counts or final estimate. A decision to continue recruitment conveys information about the rule’s application; it does not replace the outcome analysis or communicate precision.

The single-group structure highlights the distinction between describing an outcome and estimating a comparative effect. Counts within the 6MP/MTX group can describe that group, but without a comparator they cannot show how outcomes differ from another approach. That distinction is central when interpreting phase II results, especially when the registry’s primary numerical result is unavailable.

Finally, the record demonstrates the limits of registry-level safety summaries. It lists affected participants, selected serious event percentages, and deaths, but lacks some context required to interpret denominators, event timing, and causality. Statistical interpretation depends not only on the presence of numbers but also on how outcomes were defined, who was analyzed, and what uncertainty and comparison the design can support.

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 most important limitation for interpretation is that the registry does not report the primary response result. The record gives the endpoint definition and says that the first-stage threshold was met, but does not provide the final response count, denominator, proportion, or uncertainty interval. The registry lists zero analyses, and the detailed statistical analysis plan is not reported in the registry record.

The single-group design has no concurrent comparator. Masking is listed as none, and allocation is listed as NA. The design therefore cannot provide a randomized comparison of the regimen with another intervention. The registry information also does not report detailed eligibility criteria, so the population cannot be characterized beyond the stated breast or ovarian cancer and known BRCA mutation status.

The endpoint population is defined by completion of at least 4 out of 8 weeks of medication and an 8-week RECIST assessment, with early discontinuation due to progression also treated as evaluable. The number of evaluable participants is not reported. Handling of missing assessments for other reasons, use of imputation, sensitivity analyses, and any intention-to-treat analysis are not reported in the registry record.

The safety summary has limited context. The record lists counts at risk and affected, percentages for selected serious adverse event terms, and 52 deaths, but does not report all denominators, detailed event-counting methods, or enough context to attribute deaths or events to treatment. The registry also lists quality of life as a secondary outcome without reporting its result. These omissions limit both efficacy and safety interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Clinical Trial in Patients With Breast Cancer Susceptibility Gene (BRCA) Defective Tumours — NCT01432145.
• Registry record last updated 2019-07-09; status last verified 2018-06.
• Results first posted 2019-05-17.
• 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

NCT01432145 is a completed phase II, single-group study sponsored by the University of Oxford. The registry lists enrollment of 74, a start date of 2011-05, and primary completion in 2014-12. Participants with breast or ovarian cancer and known BRCA mutations received 6-mercaptopurine 55mg/m2 per day and methotrexate 15mg/m2 per week.

The primary endpoint was response at 8 weeks under RECIST version 1.1. Complete response, partial response, and stable disease were counted as response; progressive disease was counted as non-response. The record says the first-stage threshold was met, but does not report the final response count or proportion. It lists zero analyses.

Safety fields list 67 at risk and 33 affected for serious adverse events, 67 at risk and 46 affected for other adverse events, selected serious event percentages, and 52 deaths. Further context for interpreting those figures is not reported in the registry record.