This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer (NCT00976989), a randomized phase 2 study. The primary outcome is Safety: Percentage of Participants With Symptomatic Cardiac Events as Assessed by the Investigator.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00976989 |
| Phase | Phase 2 |
| Condition | Breast Cancer |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 225 |
| Arms in the primary outcome | 3 |
| Lead sponsor | Hoffmann-La Roche |
| Results posted | Yes |
2. Clinical Question
Population
Participants with locally advanced, inflammatory, or early stage HER2-positive breast cancer. The primary safety population included participants who were randomized and received study drug.
Intervention
Pertuzumab plus trastuzumab with an anthracycline-based chemotherapy regimen given concomitantly, or with a non-anthracycline-based chemotherapy regimen given concomitantly.
Comparator
Pertuzumab plus trastuzumab with anthracycline-based chemotherapy given sequentially: FEC first, followed by docetaxel with the antibodies.
Primary question
What percentage of participants in each regimen had investigator-assessed symptomatic cardiac events, including symptomatic left ventricular systolic dysfunction, from baseline up to approximately 3.5 years?
The trial compared three treatment sequences before surgery. In one arm, pertuzumab and trastuzumab were given with FEC for the first three cycles and with docetaxel for the next three. A second arm gave FEC first, then docetaxel with both antibodies. The third arm combined both antibodies with docetaxel and carboplatin for six cycles. The registry describes these as neoadjuvant regimens and includes subsequent trastuzumab therapy after surgery in the arm descriptions.
The primary question is a safety comparison, not a direct test of tumor response or survival. Its endpoint focuses on symptomatic cardiac events assessed by the investigator. The registry also lists efficacy outcomes, including pathological response and clinical response, as well as surgery and time-to-event outcomes. These provide context about other measured outcomes, but they do not change the primary endpoint's safety focus.
The registry record does not report a formal hypothesis specifying which regimen should have fewer cardiac events, a clinically important difference, or a sample-size justification for the primary endpoint. The posted comparisons use the concomitant anthracycline-based regimen as the reference for the two other arms.
3. Trial Design
This was a randomized, parallel-group, phase II study with no masking. It enrolled 225 participants and is recorded as completed. The registry lists breast cancer as the condition and describes the intended population as people with locally advanced, inflammatory, or early stage HER2-positive breast cancer. The registry record does not report the method used to generate the randomization sequence, allocation concealment, or the allocation ratio.
All three groups received pertuzumab and trastuzumab. The first group received FEC with the antibodies during the first three cycles, then docetaxel with the antibodies during the next three cycles. The second group received FEC for the first three cycles, followed by docetaxel with the antibodies for the next three cycles. The third group received docetaxel and carboplatin with both antibodies for six cycles. These treatments were described as neoadjuvant therapy, before surgery. The arm descriptions also specify trastuzumab after surgery, with the planned cycles differing between arms.
The primary endpoint was assessed in a safety population defined as randomized participants who received study drug. The arm-level primary safety results were 0.0% for concomitant anthracycline-based chemotherapy, 2.7% for sequential anthracycline-based chemotherapy, and 1.3% for concomitant non-anthracycline chemotherapy. The reported safety denominators were 72, 75, and 76, respectively.
The registry lists a primary safety assessment from baseline up to approximately 3.5 years. It also lists efficacy outcomes assessed during treatment or at surgery, along with survival outcomes. The registry record does not report detailed follow-up procedures, adherence, treatment discontinuation, or the handling of participants with incomplete endpoint data.
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
| Stage | T+P Concomitant Anthracycline-based Chemotherapy | T+P Sequential Anthracycline-based Chemotherapy | T+P Concomitant Non-Anthracycline Chemotherapy |
|---|---|---|---|
| STARTED | 73 | 75 | 77 |
| COMPLETED | 60 | 63 | 60 |
| NOT COMPLETED | 13 | 12 | 17 |
Reasons for not completing this period:
| Reason | T+P Concomitant Anthracycline-based Chemotherapy | T+P Sequential Anthracycline-based Chemotherapy | T+P Concomitant Non-Anthracycline Chemotherapy |
|---|---|---|---|
| Violation of Selection Criteria at Entry | 1 | 0 | 1 |
| Death | 5 | 7 | 10 |
| Refused Treatment | 4 | 3 | 5 |
| Failure to Return | 2 | 1 | 0 |
| Recurrence of Disease | 0 | 1 | 0 |
| Other | 1 | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who were randomized and received study drug.
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.
Population: Safety population included all participants who were randomized and received study drug.
| Characteristic | Unit | T+P Concomitant Anthracycline-based Chemotherapy | T+P Sequential Anthracycline-based Chemotherapy | T+P Concomitant Non-Anthracycline Chemotherapy | Total |
|---|---|---|---|---|---|
| Participants analysed | 73 | 75 | 77 | 225 | |
| Age, Continuous | years | 49.6 (SD 11.41) | 50.5 (SD 10.70) | 50.6 (SD 10.58) | 50.6 (SD 10.86) |
| Gender: Female | Participants | 73 | 75 | 77 | 225 |
| Gender: Male | Participants | 0 | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Safety: Percentage of Participants With Symptomatic Cardiac Events as Assessed by the Investigator, measured over From baseline up to approximately 3.5 years.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the percentage of participants with symptomatic cardiac events assessed by the investigator. The endpoint description identifies left ventricular systolic dysfunction (LVSD), including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events. Its timeframe is from baseline up to approximately 3.5 years. The stated safety population includes randomized participants who received study drug.
This endpoint is used to describe a clinically consequential type of cardiac safety event during and after the study treatment period. A percentage expresses how common the recorded event was within the specified safety group. It does not describe the timing, duration, reversibility, or severity distribution of every event; those details are not reported in the registry record for this primary outcome.
The observed percentages were 0.0% in the concomitant anthracycline-based arm, 2.7% in the sequential anthracycline-based arm, and 1.3% in the concomitant non-anthracycline arm. These are sparse event results: the posted comparisons identify no events in the reference arm, and only a small number in each other arm. With uncommon outcomes, percentages can change substantially when event counts are small, and uncertainty around the comparison is important to interpretation.
The endpoint is distinct from the separately listed cardiac outcome concerning symptoms associated with symptomatic LVSD. The registry does not provide enough detail to establish whether the endpoint definitions or ascertainment rules for these listed outcomes overlap. The primary measure should therefore be interpreted according to its stated definition, rather than expanded to cover all cardiac symptoms or all cardiac safety findings.
7. Results Posted in the Registry
- T+P Sequential Anthracycline-based Chemotherapy: 2.7% (2/75) versus 0.0% (0/72) on control; risk difference 2.7 percentage points (95% CI -1.0 to 6.3); unadjusted two-proportion z-test p = 0.163.
- T+P Concomitant Non-Anthracycline Chemotherapy: 1.3% (1/76) versus 0.0% (0/72) on control; risk difference 1.3 percentage points (95% CI -1.2 to 3.9); unadjusted two-proportion z-test p = 0.329.
Risk difference: T+P Sequential Anthracycline-based Chemotherapy
95% CI: -1.0 to 6.3 percentage points
Recalculated from the posted summary statistics
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.
| Secondary outcome | Type | Effect measure | Estimate (95% CI) | Planning size, 80% power |
|---|---|---|---|---|
| Efficacy: Percentage of Participants With Complete Pathological Response (pCR) | Binary Endpoint | Risk difference | -4.3 pts (-20.1 to 11.5) | 2,035 per arm |
| Efficacy: Clinical Response Rate | Binary Endpoint | Risk difference | +2.9 pts (-5.2 to 11.0) | 1,190 per arm |
| Efficacy: Percentage of Participants Achieving Breast Conserving Surgery | Binary Endpoint | Risk difference | -5.1 pts (-22.1 to 12.0) | 946 per arm |
Efficacy: Percentage of Participants With Complete Pathological Response (pCR)
- 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:
- T+P Sequential Anthracycline-based Chemotherapy: 57.3% (43/75) versus 61.6% (45/73) on control; risk difference -4.3 percentage points (95% CI -20.1 to 11.5), risk ratio 0.93 (0.71–1.21); unadjusted two-proportion z-test p = 0.593.
- T+P Concomitant Non-Anthracycline Chemotherapy: 66.2% (51/77) versus 61.6% (45/73) on control; risk difference 4.6 percentage points (95% CI -10.8 to 20.0), risk ratio 1.07 (0.84–1.37); unadjusted two-proportion z-test p = 0.558.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between T+P Sequential Anthracycline-based Chemotherapy and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between T+P Concomitant Non-Anthracycline Chemotherapy and the control. The interval gives the range of effects that remain compatible with the data.
Efficacy: Clinical Response Rate
- 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:
- T+P Sequential Anthracycline-based Chemotherapy: 94.7% (71/75) versus 91.8% (67/73) on control; risk difference 2.9 percentage points (95% CI -5.2 to 11.0), risk ratio 1.03 (0.95–1.13); unadjusted two-proportion z-test p = 0.484.
- T+P Concomitant Non-Anthracycline Chemotherapy: 89.6% (69/77) versus 91.8% (67/73) on control; risk difference -2.2 percentage points (95% CI -11.5 to 7.1), risk ratio 0.98 (0.88–1.08); unadjusted two-proportion z-test p = 0.648.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between T+P Sequential Anthracycline-based Chemotherapy and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between T+P Concomitant Non-Anthracycline Chemotherapy and the control. The interval gives the range of effects that remain compatible with the data.
Efficacy: Percentage of Participants Achieving Breast Conserving Surgery
- 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:
- T+P Sequential Anthracycline-based Chemotherapy: 16.7% (6/36) versus 21.7% (10/46) on control; risk difference -5.1 percentage points (95% CI -22.1 to 12.0), risk ratio 0.77 (0.31–1.91); unadjusted two-proportion z-test p = 0.565.
- T+P Concomitant Non-Anthracycline Chemotherapy: 27.0% (10/37) versus 21.7% (10/46) on control; risk difference 5.3 percentage points (95% CI -13.3 to 23.9), risk ratio 1.24 (0.58–2.66); unadjusted two-proportion z-test p = 0.576.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between T+P Sequential Anthracycline-based Chemotherapy and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between T+P Concomitant Non-Anthracycline Chemotherapy and the control. The interval gives the range of effects that remain compatible with the data.
The registry lists secondary outcomes spanning pathological response at surgery, clinical response during treatment, breast-conserving surgery, survival outcomes, and cardiac and other safety measures. Taken together, these outcomes broaden the description of the regimens beyond the primary safety question. They are not interchangeable: response at surgery, a clinical response during treatment, an operation, and a time-to-event measure represent different clinical events and assessment periods.
The posted secondary efficacy summaries show response percentages in all three arms, while the recalculated pairwise comparisons are uncertain. For the pathological-response comparisons, the reported confidence intervals include zero, and the unadjusted p-values do not provide clear evidence of a difference. The clinical-response and breast-conserving-surgery comparisons are also unadjusted. These broad patterns should not be collapsed into a single claim about overall benefit, because endpoints have different definitions and denominators.
The primary endpoint concerns investigator-assessed symptomatic cardiac events, whereas the secondary efficacy measures address response and surgery. A pattern in one domain does not settle the result in another. In particular, secondary efficacy summaries cannot be used to infer that the primary safety event is more or less likely, and the sparse primary safety results do not determine efficacy.
In general, multiple outcomes and comparisons create more opportunities for apparently notable findings to arise by chance. Unadjusted secondary p-values do not account for the number of outcomes or comparisons examined. The registry record does not report a multiplicity strategy or identify which secondary outcomes were confirmatory. The secondary findings should therefore be treated as exploratory descriptions rather than decisive evidence of a regimen difference.
Some secondary results have confidence intervals, while others do not in the posted record. The registry does not report the full statistical analysis or explain the availability of estimates across outcomes. This variation in reporting limits how consistently the secondary endpoints can be compared and how much weight each should carry alongside the primary result.
Secondary outcomes registered for this trial, for reference (only those above were recalculated):
- Efficacy: Percentage of Participants With Complete Pathological Response (pCR)
- Efficacy: Clinical Response Rate
- Efficacy: Time to Clinical Response
- Efficacy: Percentage of Participants Achieving Breast Conserving Surgery
- Efficacy: Percentage of Participants Without an Overall Survival (OS) Event
- Efficacy: Percentage of Participants Without a Disease-Free Survival (DFS) Event
- Efficacy: Percentage of Participants Without a Progression-Free Survival (PFS) Event
- Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD)
9. Statistical Interpretation
The observed primary safety percentages were low in all three groups: 0.0% with concomitant anthracycline-based chemotherapy, 2.7% with sequential anthracycline-based chemotherapy, and 1.3% with concomitant non-anthracycline chemotherapy. These figures describe events recorded in the study's defined safety population. They do not, by themselves, establish that the regimens have equivalent cardiac safety or that any regimen prevents cardiac events.
The posted comparisons use the concomitant anthracycline-based group as the reference. For sequential anthracycline-based chemotherapy, the recalculated unadjusted risk difference is 0.027, with a 95% confidence interval from -0.010 to 0.063 and p = 0.163. For concomitant non-anthracycline chemotherapy, the recalculated unadjusted risk difference is 0.013, with a 95% confidence interval from -0.013 to 0.039 and p = 0.329. Both intervals include zero, so the estimates are compatible with no difference as well as with differences in either direction. These comparisons are imprecise and do not establish a reliable distinction between the groups.
The p-values are unadjusted. They quantify how unusual data at least this different would be under a specified no-difference model, subject to the assumptions of the calculation. They are not the probability that the null hypothesis is true, and a p-value above a conventional threshold does not prove equivalence. No equivalence or non-inferiority margin is reported in the registry record.
The results also need to be read in light of the low event counts. When few events occur, a small change in the event count can noticeably alter an estimated percentage or risk difference. The confidence intervals reflect some of this uncertainty, but do not address every possible source of bias, such as differences in ascertainment or incomplete follow-up.
The registry record gives no primary-outcome analysis plan, adjustment variables, or sponsor-reported statistical comparison. The displayed comparisons are simple unadjusted recalculations from posted summary statistics; the discrepancy indicator is false. They should be regarded as descriptive comparisons, not as a substitute for a more detailed prespecified trial analysis. The record also does not report the reasons for choosing the sample size or a planned level of precision for this safety endpoint.
Overall, the posted primary data show few investigator-assessed symptomatic cardiac events and broad uncertainty around the between-group estimates. They do not support a claim of a meaningful difference, equivalence, or absence of risk. Interpretation is limited to the endpoint definition, population, and follow-up described in the registry record.
10. Statistical Methods Explained
What kind of outcome is this? The primary outcome is a binary event summarized as a percentage of participants. Each participant is classified as having or not having the specified symptomatic cardiac event during the stated assessment period. The percentages are arm-level summaries; they do not incorporate event timing or the number of repeated events for a participant.
What is a risk difference? In general, a risk difference subtracts the event proportion in one group from the event proportion in another. A value of zero corresponds to equal observed proportions. Positive or negative values indicate the direction of the comparison according to the order used. The posted comparisons use the concomitant anthracycline-based regimen as the reference and give risk differences of 0.027 for the sequential anthracycline-based comparison and 0.013 for the concomitant non-anthracycline comparison. These are unadjusted recalculations from the posted summary statistics.
What does the confidence interval add? In general, a confidence interval gives a range of values compatible with the data under the method's assumptions. It describes uncertainty in an estimate; it is not a range containing a fixed proportion of individual participants or a probability statement about the true value. The primary comparison intervals run from -0.010 to 0.063 and from -0.013 to 0.039. Because each includes zero, the observed data do not clearly distinguish a difference from no difference. The interval widths also indicate that the estimates do not pin down a narrow range of possible effects.
How should the p-values be read? The unadjusted p-values are 0.163 and 0.329 for the comparisons. In general, a p-value measures the compatibility of observed data with a null model, assuming the model and its conditions are appropriate. It does not measure the size or clinical importance of a difference and is not the probability that a treatment has no effect. A nonsignificant result is not proof that groups are the same. The registry does not report an equivalence margin or a non-inferiority framework.
Why does event rarity matter? In general, estimates based on few events are unstable: a small change in the event count can appreciably change the observed percentage. Zero observed events in a group does not show that the underlying event risk is zero. Sparse data also make it harder to estimate a contrast precisely. The confidence intervals are therefore central to reading these results, not an optional add-on to the percentages.
What is and is not adjusted? The comparisons are unadjusted and rely on summary event proportions. The registry record does not report adjustment for baseline characteristics, stratification factors, or other covariates for the primary endpoint. It also does not report a sponsor analysis for these comparisons. The recalculated comparisons are not evidence that a planned analysis used the same procedure; the analysis plan is not reported.
How do planning illustrations differ from trial power? The secondary-outcome planning illustrations use the observed effect as their starting point. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. For example, the pathological-response comparison with sequential anthracycline-based chemotherapy lists 2,035 participants per arm for 80% power when planning for 100% of the observed effect, and 3,603 when planning for 75% of that effect. These are hypothetical sample-size illustrations, not observed power and not the trial's design justification. The registry record does not report the trial's own sample-size calculation.
What can these methods establish? The displayed statistics describe the observed groups and quantify uncertainty under the calculation assumptions. They do not establish causality beyond the limitations of the trial design and its reporting, and they do not resolve missing-data, multiplicity, or measurement questions for which the registry record gives no method. Statistical significance, precision, clinical importance, and safety are related but distinct considerations.
11. Confidence Intervals and Precision
The primary endpoint has very few observed events: the posted percentages are 0.0%, 2.7%, and 1.3% across the three arms. In this setting, the point estimates alone give a limited picture. A zero observed percentage in one arm does not mean that the underlying event rate is known to be zero, and small event counts make comparisons especially sensitive to individual outcomes.
The risk-difference confidence interval for sequential versus concomitant anthracycline-based chemotherapy is -0.010 to 0.063. For concomitant non-anthracycline versus concomitant anthracycline-based chemotherapy, it is -0.013 to 0.039. Each interval includes zero, as well as values on both sides of zero. Thus, the data are compatible with no difference and also with some difference in either direction. The intervals do not support a precise estimate of the contrast.
In general, a confidence interval reflects sampling uncertainty under the method used. It does not correct for incomplete reporting, bias in event assessment, or other design limitations. The registry record does not report a confidence interval method for the primary endpoint, so the posted intervals should be read as the recalculated estimates rather than attributed to a specified sponsor analysis.
The secondary pathological-response comparisons also have confidence intervals that include zero. Their breadth illustrates that the observed arm differences are estimated with uncertainty, rather than establishing a clear separation between regimens. The secondary outcome record does not provide sponsor-reported analyses for these comparisons.
Precision is not the same as clinical importance. A narrow interval can still include effects that matter clinically, and a wide interval may cover both small and more substantial differences. The registry record does not give thresholds for a clinically important difference in the primary endpoint. Consequently, it is not possible to use these results to declare the regimens equivalent or to determine whether a possible difference would be important.
12. Multiplicity, Missing Data and Analysis Populations
The registry record lists 12 outcome measures and includes 10 posted secondary outcomes, but it does not report how the trial handled multiplicity. There is no stated hierarchy of endpoints, gatekeeping procedure, adjustment method, or distinction between confirmatory and exploratory secondary hypotheses. When several outcomes and pairwise comparisons are examined, unadjusted p-values can overstate the strength of evidence if interpreted as though only one comparison had been planned.
The posted comparison p-values are unadjusted. This applies to the primary comparisons and to the displayed secondary comparisons. No adjustment for multiple testing is reported. The registry record also does not report interim analyses or a stopping rule, so no conclusions about interim monitoring can be drawn from the record.
The primary safety population is defined as randomized participants who received study drug. That definition is not the same as an intention-to-treat population including every randomized participant regardless of treatment received. The registry record does not report whether other analyses used an intention-to-treat, per-protocol, or other population definition. Nor does it give a detailed flow of participants through randomization, treatment, surgery, and outcome assessment.
Missing-data methods are not reported in the registry record. It does not describe whether missing endpoint values were imputed, treated as non-events, excluded from the denominator, or handled through another approach. Denominators differ across posted outcomes, but the record does not explain the reasons for those differences. The available information therefore cannot establish whether missingness could have affected the estimates.
The record also does not report adjustment for baseline characteristics, a detailed analysis plan, or the protocol's sample-size justification. These absences matter because they limit assessment of prespecification, selective reporting, and the robustness of the displayed comparisons. They should be treated as reporting gaps, not as evidence that a particular method was or was not used in the conduct of the trial.
13. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| T+P Concomitant Anthracycline-based Chemotherapy | 23 | 72 | 31.9% |
| T+P Sequential Anthracycline-based Chemotherapy | 18 | 75 | 24.0% |
| T+P Concomitant Non-Anthracycline Chemotherapy | 31 | 76 | 40.8% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| T+P Concomitant Anthracycline-based Chemotherapy | 72 of 72 |
| T+P Sequential Anthracycline-based Chemotherapy | 73 of 75 |
| T+P Concomitant Non-Anthracycline Chemotherapy | 76 of 76 |
Most frequent serious adverse event terms
| Event term | Organ system | T+P Concomitant Anthracycline-based Chemotherapy | T+P Sequential Anthracycline-based Chemotherapy | T+P Concomitant Non-Anthracycline Chemotherapy |
|---|---|---|---|---|
| Febrile Neutropenia | Blood and lymphatic system disorders | 10 of 72 | 4 of 75 | 11 of 76 |
| Diarrhoea | Gastrointestinal disorders | 1 of 72 | 3 of 75 | 4 of 76 |
| Neutropenia | Blood and lymphatic system disorders | 2 of 72 | 3 of 75 | 1 of 76 |
| Left ventricular dysfunction | Cardiac disorders | 1 of 72 | 3 of 75 | 1 of 76 |
| Pneumonia | Infections and infestations | 2 of 72 | 0 of 75 | 2 of 76 |
| Neutropenic infection | Infections and infestations | 0 of 72 | 2 of 75 | 1 of 76 |
| Drug hypersensitivity | Immune system disorders | 1 of 72 | 0 of 75 | 2 of 76 |
| Leukopenia | Blood and lymphatic system disorders | 2 of 72 | 0 of 75 | 0 of 76 |
| Thrombocytopenia | Blood and lymphatic system disorders | 0 of 72 | 0 of 75 | 2 of 76 |
| Wound infection | Infections and infestations | 0 of 72 | 1 of 75 | 1 of 76 |
Most frequent non-serious adverse event terms
| Event term | Organ system | T+P Concomitant Anthracycline-based Chemotherapy | T+P Sequential Anthracycline-based Chemotherapy | T+P Concomitant Non-Anthracycline Chemotherapy |
|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | 46 of 72 | 44 of 75 | 55 of 76 |
| Alopecia | Skin and subcutaneous tissue disorders | 35 of 72 | 39 of 75 | 42 of 76 |
| Nausea | Gastrointestinal disorders | 38 of 72 | 41 of 75 | 34 of 76 |
| Neutropenia | Blood and lymphatic system disorders | 36 of 72 | 33 of 75 | 37 of 76 |
| Fatigue | General disorders | 30 of 72 | 28 of 75 | 33 of 76 |
| Vomiting | Gastrointestinal disorders | 29 of 72 | 27 of 75 | 30 of 76 |
| Anaemia | Blood and lymphatic system disorders | 14 of 72 | 8 of 75 | 29 of 76 |
| Headache | Nervous system disorders | 20 of 72 | 15 of 75 | 16 of 76 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 18 of 72 | 18 of 75 | 11 of 76 |
| Dyspepsia | Gastrointestinal disorders | 19 of 72 | 9 of 75 | 17 of 76 |
Serious events with the highest arm-level rate: febrile neutropenia (14.5%), diarrhoea (5.3%), neutropenia (4.0%), left ventricular dysfunction (4.0%), leukopenia (2.8%).
The primary safety outcome is the percentage with investigator-assessed symptomatic cardiac events, including the specified symptomatic LVSD grades. Separately, the registry reports serious adverse events affecting 23 of 72 participants in the concomitant anthracycline-based group, 18 of 75 in the sequential anthracycline-based group, and 31 of 76 in the concomitant non-anthracycline group. These are broader serious-adverse-event summaries and should not be mistaken for counts of the primary cardiac endpoint.
The registry lists febrile neutropenia at 14.5% as the most frequent serious adverse event term, followed by diarrhoea at 5.3%, neutropenia and left ventricular dysfunction at 4.0% each, and leukopenia and pneumonia at 2.8% each. The record does not say whether these terms are mutually exclusive, how recurrent events were handled, or whether the percentages use a common denominator. They describe reported event terms, not comparative treatment effects.
The registry does not report a deaths figure in the adverse-event summary. The serious-event counts should be read descriptively: they do not establish that one regimen is safer, especially without an adjusted comparison and fuller information about event definitions, follow-up, and missing data.
14. What the Result Does, and Does Not, Mean
The posted primary results establish what was recorded in this trial's safety population: investigator-assessed symptomatic cardiac events were uncommon, with an observed percentage of 0.0% in the concomitant anthracycline-based arm, 2.7% in the sequential anthracycline-based arm, and 1.3% in the concomitant non-anthracycline arm. The recalculated comparisons are uncertain, and their confidence intervals include no difference.
These findings do not establish that the three regimens have equivalent safety. Equivalence requires a prespecified margin and an analysis designed to assess whether the interval excludes differences larger than that margin; neither is reported in the registry record. Nor do the findings establish that any regimen eliminates cardiac risk. A zero observed event percentage is not proof of zero underlying risk.
The results also do not establish that one regimen is more effective than another. The secondary response and surgery outcomes provide additional descriptive information, but their unadjusted comparisons do not constitute definitive evidence of superiority. Survival outcomes are listed among the secondary measures, but detailed results for those measures are not included in the posted results summarized in the record.
Randomization supports comparisons between assigned groups, but interpretation still depends on how randomization was implemented, how outcomes were measured, and how missing observations were handled. Those details are not reported in the registry record. The primary safety population includes participants who were randomized and received study drug, and the record does not specify the analysis population used for every other outcome.
In general, a trial result is strongest for the outcomes, population, follow-up, and analysis that were prespecified and fully reported. Here, the record provides arm-level results and simple unadjusted comparisons, but not a complete analysis plan or detailed missing-data methods. The appropriate conclusion is therefore descriptive: few primary cardiac events were recorded, and the available comparisons are not precise enough to establish a meaningful between-regimen difference or equivalence.
15. Why This Trial Matters Statistically
This trial raises a statistical challenge common in safety comparisons: the event of interest is uncommon, yet the clinical question concerns differences among several treatment regimens. Sparse events make estimates sensitive to small changes in the observed counts. As a result, percentages can look distinct while the comparative uncertainty remains substantial.
The randomized, parallel-group design allows the regimens to be compared within one study, and the three arms vary in how anthracycline-based chemotherapy is sequenced or whether a non-anthracycline regimen is used. That structure makes the safety question relevant to comparative evaluation, but does not by itself ensure that the available sample is sufficient to estimate rare harms precisely. The registry record does not report a sample-size justification for the primary safety endpoint.
The trial also illustrates why a point estimate and a significance test are not enough. The primary risk-difference intervals include zero, and the p-values are unadjusted. These statistics do not establish equivalence, and they leave considerable uncertainty about the possible size and direction of the group differences. Describing that uncertainty is more informative than treating a nonsignificant result as proof that the regimens are alike.
There are multiple secondary endpoints across response, surgery, survival, and safety. Without a reported multiplicity strategy, these outcomes add breadth but also complicate interpretation. Their unadjusted comparisons should not be mistaken for a set of independent confirmatory tests.
Finally, this record demonstrates the importance of complete reporting. Details about randomization, missing data, analysis populations beyond the primary safety population, and the statistical analysis plan would help readers judge robustness. Their absence does not invalidate the posted data, but it limits how far statistical conclusions can be taken.
16. 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 safety endpoint is based on few recorded events, which limits precision. The arm percentages are descriptive, and the recalculated intervals remain compatible with no difference as well as differences in either direction. The registry record does not report a clinically important threshold against which to judge the estimates.
The trial was open label, with no masking. The primary event was assessed by the investigator, so the record does not establish whether assessment was centrally reviewed or otherwise standardized. The registry does not report detailed event adjudication procedures or how the endpoint relates to the separately listed cardiac outcome associated with symptomatic LVSD.
The registry record does not report the randomization sequence method, allocation concealment, a detailed participant flow, or baseline characteristics needed to assess group comparability. It also does not state how missing data were handled or why denominators vary across outcomes. These omissions limit assessment of selection, measurement, and missing-data risks.
The statistical analysis plan, multiplicity approach, and sample-size justification are not reported. Comparisons displayed for the primary and secondary outcomes are unadjusted recalculations, and secondary outcomes have no reported analyses in the record. The record therefore does not establish whether the displayed comparisons match prespecified sponsor analyses.
Follow-up for the primary endpoint is described as extending from baseline up to approximately 3.5 years, but the record does not provide detailed follow-up completeness or participant-level event timing. Survival outcomes are listed, but full results are not included among the posted secondary summaries. Serious adverse-event term percentages are reported without enough detail to infer whether terms overlap or how recurrent events were counted.
17. Related Tutorials
18. Related Statistical Calculators
19. Sources
- ClinicalTrials.gov: A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer — NCT00976989.
- Registry record last updated 2017-02-06; status last verified 2016-05.
- Results first posted 2016-06-20.
- 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.
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20. Record Summary
NCT00976989 is a completed randomized, open-label, parallel-group phase II study of three neoadjuvant regimens containing pertuzumab and trastuzumab for participants with HER2-positive breast cancer. The registry lists enrollment of 225 and describes concomitant and sequential anthracycline-based regimens alongside a concomitant non-anthracycline regimen.
The primary endpoint was investigator-assessed symptomatic cardiac events, including specified symptomatic LVSD, from baseline up to approximately 3.5 years. The posted arm percentages were 0.0%, 2.7%, and 1.3%. Recalculated unadjusted risk differences have confidence intervals that include zero, so the available estimates do not establish a clear difference or equivalence.
The registry also lists secondary response, surgery, survival, and safety outcomes. A multiplicity strategy, missing-data methods, detailed analysis plan, and primary-endpoint sample-size justification are not reported in the registry record.