Breast Cancer
Conditions
Brief summary
This single arm study will assess the efficacy and safety of a combination of Avastin and docetaxel following cyclophosphamide and doxorubicin, in patients with HER2 negative operable breast cancer. Patients will receive 4 x 3 week cycles of chemotherapy with doxorubicin (60mg/m2 iv on day 1 of each cycle) and cyclophosphamide (600mg/m2 iv on day 1 of each cycle). They will then receive 4 x 3 week cycles of docetaxel (75mg/m2 on day 1 of each cycle) in combination with Avastin (15mg/kg on day 1 of each cycle). The anticipated time on study treatment is 3-12 months, and the target sample size is \<100 individuals.
Interventions
DRUGbevacizumab [Avastin]
15mg/kg iv on day 1 of each 3 week cycle
DRUGDocetaxel
75mg/m2 iv on day 1 of each 3 week cycle
DRUGStandard chemotherapy
As prescribed
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* female patients, \>=18 years of age; * primary HER2-negative operable breast cancer; * tumor \>2cm in size; * ECOG performance status 0-1.
Exclusion criteria
* previous treatment for breast cancer; * metastatic disease; * current or recent (within 10 days of first dose of Avastin) use of aspirin (\>325mg/day) or full-dose anticoagulants for therapeutic purposes; * clinically significant cardiovascular disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Pathological Complete Response (pCR) | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria: 1) the primary tumor was Grade 5 (no malignant cells identified at the location of the primary tumor (ductal carcinoma in situ may be present); 2) no involvement was identified in the lymph nodes; 3) the tumour size at evaluation of the surgical piece was 0 centimeters (cm); and 4) the pathological staging of the tumour from the surgical piece was pT0pN0pM0, the stage is not applicable (NA). It will only be considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Clinical Response | Within 28 days of enrollment, Weeks 12 and 24 | Overall clinical response is the best response obtained through physical examination and/or radiological tests after completion of chemotherapy cycles. The percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) and was categorized as clinical response (CR+PR) or clinical benefit (CR+PR+ no change \[NC\]). Per RECIST, CR was defined as disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR was defined as greater than or equal to (≥)30 percent (%) decrease under baseline of the sum of the longest diameter (LD) of all target lesions. No unequivocal progression of non-target disease. No new lesions. Complete and partial responses must have been confirmed no less than 4 weeks after the criteria for response were first met. |
| Percentage of Participants With Breast-Conserving Surgery | Week 24 | Breast-conserving surgery was defined as lumpectomy + lymphadenectomy (LA), segmentectomy + LA, quadrantectomy + LA, or other (including sentinal node extirpation tumorectomy). |
| Percentage of Participants With pCR by Proliferation of Ki67 | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. Biomarker Ki67 proliferation was defined as low (less than \[\<\]15% ) and high (≥15%). |
| Percentage of Participants With pCR by Kisspeptin (KISS1) Amplification | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. KISS1 amplification was defined as 1 (aneuploid), 2 (normal), 4 (amplification), or NE (not evaluated). |
| Percentage of Participants With pCR by KISS1 Protein Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. KISS1 protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated). |
| Percentage of Participants With pCR by Vascular Endothelial Growth Factor Receptor (VEGFR) Amplification | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEFGR amplification was defined as 1 (aneuploid), 2 (normal), 4 (amplification), or NE (not evaluated). |
| Percentage of Participants With pCR by VEGFR Protein Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEGFR protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated). |
| Percentage of Participants With pCR by Hypoxia Inducible Factor (HIF) Protein Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. HIF protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated). |
| Percentage of Participants With pCR by Endothelial Nitric Oxide Synthase (ENOS) Protein Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. ENOS protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated). |
| Percentage of Participants With pCR by Angiotension Protein Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. Angiotensin protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated). |
| Percentage of Participants With pCR by Vascular Endothelial Growth Factor (VEGF) Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEGF gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by VEGFR Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEGFR gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by Phosphorylated AKT (pAKT) Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. pAKT gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by HIF Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. HIF gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by Insulin-Like Growth Factor (IGF) Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. IGF gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by ENOS Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. ENOS gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by Phosphorylated MAP Kinase (pMAPK) Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. pMAPK gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by Angiotensin II Receptor Type I (AGTR) Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. AGTR gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by KISS1 Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. KISS1 gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
| Percentage of Participants With pCR by RKISS1 Gene Expression | After Week 24 (surgery) | The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. RKISS1 gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0). |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel Participants received doxorubicin 60 mg/m\^2 IV followed by cyclophosphamide 600 mg/m\^2 IV on Day 1, repeated every 3 weeks for a maximum of 4 cycles. Participants then received bevacizumab 15 mg/kg IV followed by docetaxel 75 mg/m\^2 IV on Day 1, repeated every 3 weeks for a maximum of 4 cycles. | 72 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Disease progression | 1 |
| Overall Study | Investigator criteria | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel |
|---|---|
| Age, Continuous | 47.22 years STANDARD_DEVIATION 9.85 |
| Sex/Gender, Customized Female | 72 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 71 / 72 |
| serious Total, serious adverse events | 13 / 72 |
Outcome results
Primary
Percentage of Participants With Pathological Complete Response (pCR)
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria: 1) the primary tumor was Grade 5 (no malignant cells identified at the location of the primary tumor (ductal carcinoma in situ may be present); 2) no involvement was identified in the lymph nodes; 3) the tumour size at evaluation of the surgical piece was 0 centimeters (cm); and 4) the pathological staging of the tumour from the surgical piece was pT0pN0pM0, the stage is not applicable (NA). It will only be considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes.
Time frame: After Week 24 (surgery)
Population: Population evaluable for anatomopathological response: participants who satisfied all inclusion criteria and none of the exclusion criteria, received at least 2 cycles of chemotherapy treatment, and were evaluated pathologically.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With Pathological Complete Response (pCR) | 24.2 percentage of participants |
Secondary
Percentage of Participants With Breast-Conserving Surgery
Breast-conserving surgery was defined as lumpectomy + lymphadenectomy (LA), segmentectomy + LA, quadrantectomy + LA, or other (including sentinal node extirpation tumorectomy).
Time frame: Week 24
Population: ITT population; only those participants who underwent surgery were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With Breast-Conserving Surgery | 62.7 percentage of participants |
Secondary
Percentage of Participants With Objective Clinical Response
Overall clinical response is the best response obtained through physical examination and/or radiological tests after completion of chemotherapy cycles. The percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) and was categorized as clinical response (CR+PR) or clinical benefit (CR+PR+ no change \[NC\]). Per RECIST, CR was defined as disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR was defined as greater than or equal to (≥)30 percent (%) decrease under baseline of the sum of the longest diameter (LD) of all target lesions. No unequivocal progression of non-target disease. No new lesions. Complete and partial responses must have been confirmed no less than 4 weeks after the criteria for response were first met.
Time frame: Within 28 days of enrollment, Weeks 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With Objective Clinical Response | CR+PR | 88.9 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With Objective Clinical Response | CR+PR+NC | 98.6 percentage of participants |
Secondary
Percentage of Participants With pCR by Angiotensin II Receptor Type I (AGTR) Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. AGTR gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Angiotensin II Receptor Type I (AGTR) Gene Expression | Gene expression above housekeeping level (n=0) | NA percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Angiotensin II Receptor Type I (AGTR) Gene Expression | Gene expression below housekeeping level (n=33) | 30.3 percentage of participants |
Secondary
Percentage of Participants With pCR by Angiotension Protein Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. Angiotensin protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Angiotension Protein Expression | No expression (n=14) | 7.1 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Angiotension Protein Expression | Normal (n=1) | 0.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Angiotension Protein Expression | Augmented expression (n=11) | 63.6 percentage of participants |
p-value: 0.0074Fisher Exact
Secondary
Percentage of Participants With pCR by Endothelial Nitric Oxide Synthase (ENOS) Protein Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. ENOS protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Endothelial Nitric Oxide Synthase (ENOS) Protein Expression | No expression (n=24) | 29.2 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Endothelial Nitric Oxide Synthase (ENOS) Protein Expression | Normal (n=10) | 40.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Endothelial Nitric Oxide Synthase (ENOS) Protein Expression | Augmented expression (n=4) | 25.0 percentage of participants |
p-value: 0.8696Fisher Exact
Secondary
Percentage of Participants With pCR by ENOS Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. ENOS gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by ENOS Gene Expression | Gene expression above housekeeping level (n=1) | 0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by ENOS Gene Expression | Gene expression below housekeeping level (n=33) | 33.3 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percentage of Participants With pCR by HIF Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. HIF gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by HIF Gene Expression | Gene expression above housekeeping level (n=9) | 44.4 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by HIF Gene Expression | Gene expression below housekeeping level (n=25) | 28.0 percentage of participants |
p-value: 0.4254Fisher Exact
Secondary
Percentage of Participants With pCR by Hypoxia Inducible Factor (HIF) Protein Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. HIF protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Hypoxia Inducible Factor (HIF) Protein Expression | No expression (n=25) | 40.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Hypoxia Inducible Factor (HIF) Protein Expression | Normal (n=8) | 12.5 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Hypoxia Inducible Factor (HIF) Protein Expression | Augmented expression (n=5) | 60.0 percentage of participants |
p-value: 0.223Fisher Exact
Secondary
Percentage of Participants With pCR by Insulin-Like Growth Factor (IGF) Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. IGF gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Insulin-Like Growth Factor (IGF) Gene Expression | Gene expression above housekeeping level (n=0) | NA percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Insulin-Like Growth Factor (IGF) Gene Expression | Gene expression below housekeeping level (n=34) | 32.4 percentage of participants |
Secondary
Percentage of Participants With pCR by KISS1 Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. KISS1 gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by KISS1 Gene Expression | Gene expression above housekeeping level (n=1) | 0.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by KISS1 Gene Expression | Gene expression below housekeeping level (n=33) | 33.3 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percentage of Participants With pCR by KISS1 Protein Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. KISS1 protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by KISS1 Protein Expression | No expression (n=18) | 27.8 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by KISS1 Protein Expression | Normal (n=3) | 66.7 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by KISS1 Protein Expression | Augmented expression (n=4) | 50.0 percentage of participants |
p-value: 0.3613Fisher Exact
Secondary
Percentage of Participants With pCR by Kisspeptin (KISS1) Amplification
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. KISS1 amplification was defined as 1 (aneuploid), 2 (normal), 4 (amplification), or NE (not evaluated).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Kisspeptin (KISS1) Amplification | Anueploid (n=8) | 12.5 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Kisspeptin (KISS1) Amplification | Normal (n=13) | 30.77 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Kisspeptin (KISS1) Amplification | Amplification (n=2) | 50.0 percentage of participants |
p-value: 0.4864Chi-squared
Secondary
Percentage of Participants With pCR by Phosphorylated AKT (pAKT) Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. pAKT gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Phosphorylated AKT (pAKT) Gene Expression | Gene expression above housekeeping level (n=0) | NA percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Phosphorylated AKT (pAKT) Gene Expression | Gene expression below housekeeping level (n=34) | 32.4 percentage of participants |
Secondary
Percentage of Participants With pCR by Phosphorylated MAP Kinase (pMAPK) Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. pMAPK gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Phosphorylated MAP Kinase (pMAPK) Gene Expression | Gene expression above housekeeping level (n=30) | 33.3 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Phosphorylated MAP Kinase (pMAPK) Gene Expression | Gene expression equal to housekeeping level (n=1) | 0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Phosphorylated MAP Kinase (pMAPK) Gene Expression | Gene expression below housekeeping level (n=3) | 33.3 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percentage of Participants With pCR by Proliferation of Ki67
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. Biomarker Ki67 proliferation was defined as low (less than \[\<\]15% ) and high (≥15%).
Time frame: After Week 24 (surgery)
Population: Population evaluable for anatomopathological response with evaluable levels of the specified biomarker; data were missing for 2 participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Proliferation of Ki67 | High proliferative index (n=50) | 24.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Proliferation of Ki67 | Low proliferative index (n=15) | 13.3 percentage of participants |
p-value: 0.4915Fisher Exact
Secondary
Percentage of Participants With pCR by RKISS1 Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. RKISS1 gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by RKISS1 Gene Expression | Gene expression above housekeeping level (n=0) | NA percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by RKISS1 Gene Expression | Gene expression below housekeeping level (n=34) | 32.4 percentage of participants |
Secondary
Percentage of Participants With pCR by Vascular Endothelial Growth Factor Receptor (VEGFR) Amplification
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEFGR amplification was defined as 1 (aneuploid), 2 (normal), 4 (amplification), or NE (not evaluated).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Vascular Endothelial Growth Factor Receptor (VEGFR) Amplification | Anueploid (n=1) | 0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Vascular Endothelial Growth Factor Receptor (VEGFR) Amplification | Normal (n=18) | 33.3 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Vascular Endothelial Growth Factor Receptor (VEGFR) Amplification | Amplification (n=4) | 0 percentage of participants |
p-value: 0.6605Fisher Exact
Secondary
Percentage of Participants With pCR by Vascular Endothelial Growth Factor (VEGF) Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEGF gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Vascular Endothelial Growth Factor (VEGF) Gene Expression | Gene expression above housekeeping level (n=1) | 100.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by Vascular Endothelial Growth Factor (VEGF) Gene Expression | Gene expression below housekeeping level (n=33) | 30.3 percentage of participants |
p-value: 0.3235Fisher Exact
Secondary
Percentage of Participants With pCR by VEGFR Gene Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEGFR gene expression was defined as below the housekeeping reference level (\>0), above the housekeeping reference level (\<0), or equal to the housekeeping reference level (0).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by VEGFR Gene Expression | Gene expression above housekeeping level (n=7) | 0.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by VEGFR Gene Expression | Gene expression below housekeeping level (n=27) | 40.7 percentage of participants |
p-value: 0.0693Fisher Exact
Secondary
Percentage of Participants With pCR by VEGFR Protein Expression
The percentage of participants with pCR was determined by anatomopathological study after completion of 8 cycles of study treatment. The anatomopathological study of the surgical piece was performed and assessed according to the Miller-Payne criteria. It was only considered pCR in the case of absence of invasive tumour cells in the breast and lymph nodes. VEGFR protein expression was defined as 0 (no expression), 1 (normal), 2 (augmented expression), or NE (not evaluated).
Time frame: After Week 24 (surgery)
Population: Only those participants evaluated for the specified biomarker were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by VEGFR Protein Expression | No expression (n=7) | 28.6 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by VEGFR Protein Expression | Normal (n=5) | 40.0 percentage of participants |
| Doxorubicin + Cyclophosphamide/Bevacizumab + Docetaxel | Percentage of Participants With pCR by VEGFR Protein Expression | Augmented expression (n=10) | 20.0 percentage of participants |
p-value: 0.8311Fisher Exact