Triple Negative Breast Cancer
Conditions
Keywords
TRIPLE NEGATIVE BREAST CANCER, CISPLATIN, PACLITAXEL
Brief summary
This is a phase II study randomizing patients with stage I with T1 \> 1.5 cm, stage II or III triple negative breast cancer (TNBC) to preoperative cisplatin versus paclitaxel. The study is designed to evaluate the ability of the Homologous Recombination Deficiency (HRD) assay to predict pathologic response to preoperative chemotherapy.
Detailed description
Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response (residual cancer burden (RCB)-0/1) to singleagent cisplatin or paclitaxel. This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score \>=33. Crossover to an alternative chemotherapy was offered if there was inadequate response.
Interventions
DRUGCisplatin
DRUGPaclitaxel
Sponsors
Myriad Genetics, Inc.
Translational Breast Cancer Research Consortium
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants must meet the following criteria on screening examination to be eligible to participate in the study 2. Pathologic documentation of invasive breast cancer by biopsy (FNA alone is not adequate). 3. AJCC clinical stage I with T1 \> 1.5 cm, stage II or III invasive breast cancer. 4. Participants with multicentric or bilateral disease are eligible if at least one lesion meets stage eligibility criteria for the study and no tumor is HER2-positive. 5. Tumors must be HER2 negative defined as HER2 0 or 1+ by immunohistochemistry (IHC) assays and /or lack of gene amplification by FISH defined as a ratio \< 2 on invasive tumor by local review. 6. ER and PgR status by IHC must be known. Tumor must be ER and PR negative (≤5% staining) by local review. 7. Known BRCA1/2 (BReast CAncer) status is not required for study entry. However patients known to have a germline deleterious BRCA1/2 mutation should be encouraged to consider a preoperative trial specifically designed for BRCA1/2 carriers, if available. 8. Breast imaging should include imaging of the ipsilateral axilla. For subjects with a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be performed to confirm the presence of metastatic disease in the lymph nodes. For patients with a clinically negative axilla, baseline assessment of the axilla will be performed at the discretion of the treating investigator. For patients with pathologically positive axillary lymph nodes prior to preoperative therapy, a level I and II lymph node dissection at the time of definitive surgery is recommended. 9. Patients with a prior history of contra-lateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer within the last 5 years. 10. Women ≥ 18 years of age. 11. ECOG performance status ≤1 (see Appendix A). 12. Laboratory Evaluation 1) Absolute neutrophil count (ANC) ≥ 1,500 / mm3 2) Platelet count ≥ 100,000/ mm3 3) Bilirubin ≤ 1.5x upper limit of normal (ULN), for patients with Gilbert syndrome, direct bilirubin will be measured instead of total bilirubin 4) ALT, AST ≤3.0 x ULN ALK Phos \<2.5 x ULN 5) Creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min 6) Hemoglobin ≥ 9 mg/dl 7) Use of an effective means of contraception is required in subjects of childbearing potential since study agents are known to be teratogenic. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. 8) Ability to understand and the willingness to sign a written informed consent document 9) Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy and did not receive prior chemotherapy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. 10) Patient must be willing to undergo mandatory research biopsy and blood draw. Prior to biopsy procedures patients must be able to be off medications that could increase the risk of bleeding
Exclusion criteria
1. Participants with axillary adenopathy only are not eligible for this study. 2. Prior chemotherapy: Prior non-taxane or platinum containing chemotherapy will be allowed if the prior exposure was at least 5 years ago and the exposure is thought not to potentially interact with the primary outcome of the trial or put the patient at undue risk, and should be reviewed with study PI on a case by case basis. 3. Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy. 4. Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for DCIS or breast conserving treatment and hormonal therapy for DCIS or invasive breast cancer. 5. Ongoing use of any other investigational or study agents. 6. Peripheral neuropathy of any etiology \> grade 1 (NCI CTCAE Version 4.0- Appendix B) 7. Significant hearing loss that would prevent cisplatin administration. 8. Renal dysfunction for which exposure to cisplatin would be unsafe or require cisplatin dose modification (i.e., Cre \> 1.5 mg/dl or GFR \< 60 cc/min).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). pCR is defined as RCB-0. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33. |
| Number of Pathologic Response | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33. |
| Number With Pathologic Response | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33. |
| Positive Predictive Value (PPV) of HRD Score | Evaluated after definitive breast surgery, up to 4-5 months from enrollment. | Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33. PPV was calculated as the probability of pathological response among the HRD positive group. |
Countries
United States
Participant flow
Recruitment details
From April 2014 through January 2018
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Cisplatin Cisplatin given by IV infusion at a dose of 75 mg/m2 every 3 weeks (1 cycle) for 4 cycles as preoperative chemotherapy. Participants with inadequate clinical response after 12 weeks (as judged either clinically or radiologically by a provider) were able to crossover to an alternative provider-selected preoperative chemotherapy regimen. Definitive breast surgery following no later than 42 days after administration of last chemotherapy. | 75 |
| Arm B: Paclitaxel Paclitaxel given by IV infusion at a dose of 80 mg/m2 weekly for 12 weeks (4 cycles) as neoadjuvant chemotherapy. Participants with inadequate clinical response after 12 weeks (as judged either clinically or radiologically by a provider) were able to 'crossover' to an alternative provider-selected preoperative chemotherapy regimen. Definitive breast surgery following no later than 42 days after administration of last chemotherapy. | 72 |
| Total | 147 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Preoperative Chemotherapy | Hypersensitivity during cycle 1 so therapy stopped | 0 | 2 |
| Preoperative Chemotherapy | Ineligible Prior to Starting Therapy | 1 | 0 |
| Preoperative Chemotherapy | Lost to Follow-up | 0 | 1 |
| Preoperative Chemotherapy | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Arm A: Cisplatin | Total | Arm B: Paclitaxel |
|---|---|---|---|
| Age, Continuous | 51 years | 53 years | 53.5 years |
| BRCA1/2 Status Germline and/or somatic mutation | 6 Participants | 7 Participants | 1 Participants |
| BRCA1/2 Status Germline/somatic intact | 69 Participants | 140 Participants | 71 Participants |
| Clinical lymph node status Negative | 46 Participants | 92 Participants | 46 Participants |
| Clinical lymph node status Positive | 29 Participants | 55 Participants | 26 Participants |
| Homologous Recombination Deficiency (HRD) Status HRD High (+) Status | 39 Participants | 74 Participants | 35 Participants |
| Homologous Recombination Deficiency (HRD) Status HRD Low (-) Status | 17 Participants | 30 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 11 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 19 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) White | 60 Participants | 111 Participants | 51 Participants |
| Region of Enrollment United States | 75 Participants | 147 Participants | 72 Participants |
| Sex: Female, Male Female | 75 Participants | 147 Participants | 72 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 72 | 0 / 67 |
| other Total, other adverse events | 72 / 72 | 67 / 67 |
| serious Total, serious adverse events | 11 / 72 | 19 / 67 |
Outcome results
Primary
Number of Participants With Pathologic Response by HR-deficiency (HRD) Status
Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33.
Time frame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
Population: The analysis population is comprised of all participants with evaluable tissue for HRD analysis and who completed definitive breast surgery.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Cisplatin With HRD+ | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Responder (RCB-0/1) | 9 Participants |
| Arm A: Cisplatin With HRD+ | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Non-Responder (RCB-2/3 or crossover) | 30 Participants |
| Arm A: Cisplatin With HRD- | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Non-Responder (RCB-2/3 or crossover) | 15 Participants |
| Arm A: Cisplatin With HRD- | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Responder (RCB-0/1) | 2 Participants |
| Arm B: Paclitaxel With HRD+ | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Responder (RCB-0/1) | 10 Participants |
| Arm B: Paclitaxel With HRD+ | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Non-Responder (RCB-2/3 or crossover) | 25 Participants |
| Arm B: Paclitaxel With HRD- | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Responder (RCB-0/1) | 4 Participants |
| Arm B: Paclitaxel With HRD- | Number of Participants With Pathologic Response by HR-deficiency (HRD) Status | Non-Responder (RCB-2/3 or crossover) | 9 Participants |
Comparison: In the Cisplatin treated patients, the relationship between HRD status and pathologic response was conducted by arm using a univariate logistic regression model and a likelihood ratio test with a one-sided type I error of alpha 0.05. Assuming 12.5% unevaluable, prevalence of HR deficiency 60%, 70 evaluable patients per in a given arm, there is \~80% power to detect a response rate of 52% in HR-deficient patients vs a 16% in HR non-deficient patients, corresponding to the Odds Ratio 5.7.95% CI: [0.39, 23.68]
Comparison: In the Paclitaxel treated patients, the relationship between HRD status and pathologic response was conducted by arm using a univariate logistic regression model and a likelihood ratio test with a one-sided type I error of alpha 0.05. Assuming 12.5% unevaluable, prevalence of HR deficiency 60%, 70 evaluable patients per in a given arm, there is \~80% power to detect a response rate of 37% in HR-deficient patients vs a 16% in HR non-deficient patients, corresponding to the Odds Ratio 0.62.95% CI: [0.19, 4.95]
Secondary
Number of Pathologic Response
Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33.
Time frame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Cisplatin With HRD+ | Number of Pathologic Response | Responder (RCB-0/1) | 19 Participants |
| Arm A: Cisplatin With HRD+ | Number of Pathologic Response | Non-responder (RCB-2/3 or crossover) | 53 Participants |
| Arm A: Cisplatin With HRD- | Number of Pathologic Response | Responder (RCB-0/1) | 15 Participants |
| Arm A: Cisplatin With HRD- | Number of Pathologic Response | Non-responder (RCB-2/3 or crossover) | 52 Participants |
Secondary
Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status
Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). pCR is defined as RCB-0. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33.
Time frame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
Population: The analysis population is comprised of all participants with evaluable tissue for HRD analysis and who completed definitive breast surgery.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Cisplatin With HRD+ | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | pCR | 5 Participants |
| Arm A: Cisplatin With HRD+ | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | No pCR | 34 Participants |
| Arm A: Cisplatin With HRD- | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | No pCR | 16 Participants |
| Arm A: Cisplatin With HRD- | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | pCR | 1 Participants |
| Arm B: Paclitaxel With HRD+ | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | pCR | 5 Participants |
| Arm B: Paclitaxel With HRD+ | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | No pCR | 30 Participants |
| Arm B: Paclitaxel With HRD- | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | pCR | 3 Participants |
| Arm B: Paclitaxel With HRD- | Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status | No pCR | 10 Participants |
95% CI: [0.23, 118.07]
95% CI: [0.09, 4.14]
Secondary
Number With Pathologic Response
Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33.
Time frame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Cisplatin With HRD+ | Number With Pathologic Response | pCR | 11 Participants |
| Arm A: Cisplatin With HRD+ | Number With Pathologic Response | Non-pCR | 61 Participants |
| Arm A: Cisplatin With HRD- | Number With Pathologic Response | pCR | 8 Participants |
| Arm A: Cisplatin With HRD- | Number With Pathologic Response | Non-pCR | 59 Participants |
Secondary
Positive Predictive Value (PPV) of HRD Score
Pathologic response was assessed using the MD Anderson residual cancer burden (RCB) method (Symmans et al. JCO 2007). Responders are defined as RCB 0/1 and non-responders as RCB 2/3. Participants who crossed over due inadequate clinical response after 12 weeks were counted as non-responders. HRD status was determined with baseline diagnostic tissue using the HRD assay (Myriad Genetics, Inc.; required minimum 100 mm2 of tumor tissue) which detects impaired double-strand DNA break repair. The positive threshold for HRD was a score \>/= 33. PPV was calculated as the probability of pathological response among the HRD positive group.
Time frame: Evaluated after definitive breast surgery, up to 4-5 months from enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Cisplatin With HRD+ | Positive Predictive Value (PPV) of HRD Score | .231 probability |
| Arm A: Cisplatin With HRD- | Positive Predictive Value (PPV) of HRD Score | .286 probability |