Cisplatin vs Paclitaxel for Triple Negative Breast Cancer

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01982448
• Collaborator: Myriad Genetics, Inc. (Industry), Translational Breast Cancer Research Consortium (Other)
• Enrollment: 147
• Locations: 20
• Arms: 2
• Duration (Months): 110
• Patients Per Site: 7.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Triple Negative Breast Cancer	Drug: Cisplatin; Drug: Paclitaxel	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 147 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Preoperative Cisplatin Versus Paclitaxel in Patients With Triple Negative Breast Cancer: Evaluating the Homologous Recombination Deficiency (HRD) Biomarker
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Jan 1, 2019
• Anticipated Study Completion Date: Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Cisplatin; Other Names: Platinol ®-AQ
Experimental: 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.	Drug: Paclitaxel; Other Names: Taxol

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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.

1. 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.

2. Women ≥ 18 years of age. 11. ECOG performance status ≤1 (see Appendix A). 12. Laboratory Evaluation

3. Absolute neutrophil count (ANC) ≥ 1,500 / mm3

4. Platelet count ≥ 100,000/ mm3

5. Bilirubin ≤ 1.5x upper limit of normal (ULN), for patients with Gilbert syndrome, direct bilirubin will be measured instead of total bilirubin

6. ALT, AST ≤3.0 x ULN ALK Phos <2.5 x ULN

7. Creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min

8. Hemoglobin ≥ 9 mg/dl

9. 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.

10. Ability to understand and the willingness to sign a written informed consent document

11. 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.

12. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	Indiana University- Simon Cancer Center	Indianapolis	Indiana	United States	46202
3	Johns Hopkins University	Baltimore	Maryland	United States	21287
4	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
5	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	South Shore Hospital	Weymouth	Massachusetts	United States	02190
7	Memorial Sloan Kettering Cancer Center-Basking Ridge	Basking Ridge	New Jersey	United States	07920
8	Memorial Sloan Kettering Cancer Center-Monmouth	Middletown	New Jersey	United States	07748
9	Memorial Sloan Kettering Cancer Center-Commack	Commack	New York	United States	11725
10	Memorial Sloan Kettering Cancer Center-West Harrison	Harrison	New York	United States	10604
11	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
12	Memorial Sloan Kettering Cancer Center-Rockville Centre	Rockville Centre	New York	United States	11570
13	Memorial Sloan Kettering Cancer Center-Sleepy Hollow	Sleepy Hollow	New York	United States	10591
14	University of North Carolina- Lineberger Cancer Center	Chapel Hill	North Carolina	United States	27599
15	Duke University	Durham	North Carolina	United States	27710
16	Universtiy of Pittsburgh- Magee-Womens Hospital	Pittsburgh	Pennsylvania	United States	15213
17	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
18	Baylor College of Medicine	Houston	Texas	United States	77030
19	Seattle Cancer Alliance at EvergreenHealth	Kirkland	Washington	United States	98034
20	University of Washignton	Seattle	Washington	United States	98195

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Myriad Genetics, Inc.
• Translational Breast Cancer Research Consortium

Investigators

• Principal Investigator: Erica Mayer, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 14, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Erica Mayer, MD, MPH, Principal Invesitigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01982448
• Other Study ID Numbers: 13-383; TBCRC030
• First Posted: Nov 13, 2013
• Last Update Posted: Mar 9, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Erica Mayer, MD, MPH, Principal Invesitigator, Dana-Farber Cancer Institute: TRIPLE NEGATIVE BREAST CANCER; CISPLATIN; PACLITAXEL
• Additional relevant MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Paclitaxel; Cisplatin

Study Results

Participant Flow

Recruitment Details	From April 2014 through January 2018

Arm/Group Title	Arm A: Cisplatin	Arm B: Paclitaxel
Arm/Group Description	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.	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.
Period Title: Preoperative Chemotherapy
STARTED	75	72
Eligible & Treated	72	70
Evaluable for Safety	72	68
COMPLETED	72	67
NOT COMPLETED	3	5
Period Title: Preoperative Chemotherapy
STARTED	72	67
Evaluable for Response by Homologous Recombination Deficiency (HRD)	56	48
COMPLETED	72	67
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm A: Cisplatin	Arm B: Paclitaxel	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	75	72	147
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51	53.5	53
Sex: Female, Male (Count of Participants)
Female	75 100%	72 100%	147 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	7 9.3%	4 5.6%	11 7.5%
Asian	0 0%	2 2.8%	2 1.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 10.7%	11 15.3%	19 12.9%
White	60 80%	51 70.8%	111 75.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	4 5.6%	4 2.7%
Region of Enrollment (Count of Participants)
United States	75 100%	72 100%	147 100%
BRCA1/2 Status (Count of Participants)
Germline/somatic intact	69 92%	71 98.6%	140 95.2%
Germline and/or somatic mutation	6 8%	1 1.4%	7 4.8%
Clinical lymph node status (Count of Participants)
Positive	29 38.7%	26 36.1%	55 37.4%
Negative	46 61.3%	46 63.9%	92 62.6%
Homologous Recombination Deficiency (HRD) Status (Count of Participants)
HRD High (+) Status	39 52%	35 48.6%	74 50.3%
HRD Low (-) Status	17 22.7%	13 18.1%	30 20.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Pathologic Response by HR-deficiency (HRD) Status
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis population is comprised of all participants with evaluable tissue for HRD analysis and who completed definitive breast surgery.

Arm/Group Title	Arm A: Cisplatin With HRD+	Arm A: Cisplatin With HRD-	Arm B: Paclitaxel With HRD+	Arm B: Paclitaxel With HRD-
Arm/Group Description	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. HRD+ (score >/=33)	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. HRD- (score <33)	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. HRD+ (score >/=33)	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. HRD- (score <33)
Measure Participants	39	17	35	13
Responder (RCB-0/1)	9 12%	2 2.8%	10 6.8%	4 NaN
Non-Responder (RCB-2/3 or crossover)	30 40%	15 20.8%	25 17%	9 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Cisplatin With HRD+, Arm A: Cisplatin With HRD-
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.22
	Confidence Interval	(2-Sided) 95%; 0.39 to 23.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Association between HRD status and pathologic response was measured by the odds ratio (OR).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm B: Paclitaxel With HRD+, Arm B: Paclitaxel With HRD-
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.19 to 4.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number With Pathologic Complete Response (pCR) by HR-deficiency (HRD) Status
Description	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.

Outcome Measure Data

Analysis Population Description

The analysis population is comprised of all participants with evaluable tissue for HRD analysis and who completed definitive breast surgery.

Arm/Group Title	Arm A: Cisplatin With HRD+	Arm A: Cisplatin With HRD-	Arm B: Paclitaxel With HRD+	Arm B: Paclitaxel With HRD-
Arm/Group Description	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. HRD+ (score >/=33)	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. HRD- (score <33)	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. HRD+ (score >/=33)	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. HRD- (score <33)
Measure Participants	39	17	35	13
pCR	5 6.7%	1 1.4%	5 3.4%	3 NaN
No pCR	34 45.3%	16 22.2%	30 20.4%	10 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Cisplatin With HRD+, Arm A: Cisplatin With HRD-
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.32
	Confidence Interval	(2-Sided) 95%; 0.23 to 118.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm B: Paclitaxel With HRD+, Arm B: Paclitaxel With HRD-
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.09 to 4.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Pathologic Response
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Cisplatin	Arm B: Paclitaxel
Arm/Group Description	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.	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.
Measure Participants	72	67
Responder (RCB-0/1)	19 25.3%	15 20.8%
Non-responder (RCB-2/3 or crossover)	53 70.7%	52 72.2%

4. Secondary Outcome

Title	Number With Pathologic Response
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Cisplatin	Arm B: Paclitaxel
Arm/Group Description	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.	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.
Measure Participants	72	67
pCR	11 14.7%	8 11.1%
Non-pCR	61 81.3%	59 81.9%

5. Secondary Outcome

Title	Positive Predictive Value (PPV) of HRD Score
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: Cisplatin	Arm B: Paclitaxel
Arm/Group Description	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.	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.
Measure Participants	39	35
Number [probability]	.231	.286

Adverse Events

Time Frame	AE data collected every cycle from the time of the first dose of study treatment, through the study 12 weeks of treatment until 30 days after removal from study or death, whichever occurs first. Therefore, AEs were observed up to 4 months.
Adverse Event Reporting Description	Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	Paclitaxel		Cisplatin
Arm/Group Description	Paclitaxel will be given as an IV infusion at a dose of 80mg/m2 weekly x 12 weeks (4 cycles).		Cisplatin will be given by IV at 75 mg/m2 every 3 weeks, 4 cycles.
All Cause Mortality
	Paclitaxel		Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/72 (0%)		0/67 (0%)
Serious Adverse Events
	Paclitaxel		Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/72 (15.3%)		19/67 (28.4%)
Blood and lymphatic system disorders
Leukocytosis	1/72 (1.4%)		0/67 (0%)
Gastrointestinal disorders
Nausea	0/72 (0%)		2/67 (3%)
Vomiting	0/72 (0%)		1/67 (1.5%)
General disorders
Fatigue	0/72 (0%)		3/67 (4.5%)
Investigations
Lymphocyte count decreased	1/72 (1.4%)		0/67 (0%)
Neutrophil count decreased	5/72 (6.9%)		8/67 (11.9%)
White blood cell decreased	1/72 (1.4%)		0/67 (0%)
Metabolism and nutrition disorders
Dehydration	0/72 (0%)		1/67 (1.5%)
Hypophosphatemia	2/72 (2.8%)		1/67 (1.5%)
Nasal congestion	1/72 (1.4%)		0/67 (0%)
Vascular disorders
Thromboembolic event	0/72 (0%)		3/67 (4.5%)
Other (Not Including Serious) Adverse Events
	Paclitaxel		Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/72 (100%)		67/67 (100%)
Blood and lymphatic system disorders
Anemia	37/72 (51.4%)		33/67 (49.3%)
Febrile neutropenia	0/72 (0%)		1/67 (1.5%)
Lymph node pain	0/72 (0%)		1/67 (1.5%)
Blood and lymphatic system disorders - Other	3/72 (4.2%)		5/67 (7.5%)
Cardiac disorders
Atrial fibrillation	1/72 (1.4%)		0/67 (0%)
Chest pain - cardiac	1/72 (1.4%)		2/67 (3%)
Mitral valve disease	1/72 (1.4%)		0/67 (0%)
Palpitations	3/72 (4.2%)		0/67 (0%)
Sick sinus syndrome	0/72 (0%)		1/67 (1.5%)
Sinus bradycardia	0/72 (0%)		1/67 (1.5%)
Sinus tachycardia	1/72 (1.4%)		2/67 (3%)
Ventricular arrhythmia	1/72 (1.4%)		0/67 (0%)
Cardiac disorders - Other	3/72 (4.2%)		2/67 (3%)
Ear and labyrinth disorders
Ear pain	1/72 (1.4%)		0/67 (0%)
Hearing impaired	0/72 (0%)		1/67 (1.5%)
Tinnitus	1/72 (1.4%)		21/67 (31.3%)
Tinnitus	1/72 (1.4%)		5/67 (7.5%)
Vertigo	0/72 (0%)		2/67 (3%)
Ear and labyrinth disorders - Other	0/72 (0%)		2/67 (3%)
Endocrine disorders
Hypothyroidism	1/72 (1.4%)		6/67 (9%)
Endocrine disorders - Other	0/72 (0%)		1/67 (1.5%)
Eye disorders
Blurred vision	3/72 (4.2%)		1/67 (1.5%)
Conjunctivitis	1/72 (1.4%)		1/67 (1.5%)
Dry eye	2/72 (2.8%)		2/67 (3%)
Flashing lights	1/72 (1.4%)		0/67 (0%)
Glaucoma	2/72 (2.8%)		0/67 (0%)
Watering eyes	1/72 (1.4%)		0/67 (0%)
Eye disorders - Other	2/72 (2.8%)		0/67 (0%)
Gastrointestinal disorders
Abdominal pain	6/72 (8.3%)		4/67 (6%)
Bloating	2/72 (2.8%)		2/67 (3%)
Colitis	0/72 (0%)		1/67 (1.5%)
Constipation	19/72 (26.4%)		31/67 (46.3%)
Diarrhea	23/72 (31.9%)		16/67 (23.9%)
Dry mouth	5/72 (6.9%)		2/67 (3%)
Duodenal hemorrhage	0/72 (0%)		1/67 (1.5%)
Dyspepsia	10/72 (13.9%)		6/67 (9%)
Dysphagia	0/72 (0%)		1/67 (1.5%)
Flatulence	1/72 (1.4%)		1/67 (1.5%)
Gastroesophageal reflux disease	10/72 (13.9%)		12/67 (17.9%)
Gastrointestinal pain	1/72 (1.4%)		0/67 (0%)
Hemorrhoids	1/72 (1.4%)		0/67 (0%)
Mucositis oral	6/72 (8.3%)		4/67 (6%)
Nausea	31/72 (43.1%)		57/67 (85.1%)
Oral dysesthesia	2/72 (2.8%)		1/67 (1.5%)
Oral pain	1/72 (1.4%)		0/67 (0%)
Salivary duct inflammation	0/72 (0%)		1/67 (1.5%)
Stomach pain	0/72 (0%)		1/67 (1.5%)
Vomiting	2/72 (2.8%)		13/67 (19.4%)
Gastrointestinal disorders - Other	4/72 (5.6%)		4/67 (6%)
General disorders
Chills	1/72 (1.4%)		2/67 (3%)
Edema limbs	4/72 (5.6%)		3/67 (4.5%)
Fatigue	51/72 (70.8%)		55/67 (82.1%)
Fever	1/72 (1.4%)		3/67 (4.5%)
Flu like symptoms	2/72 (2.8%)		2/67 (3%)
Infusion related reaction	8/72 (11.1%)		0/67 (0%)
Irritability	1/72 (1.4%)		0/67 (0%)
Localized edema	2/72 (2.8%)		0/67 (0%)
Non-cardiac chest pain	9/72 (12.5%)		3/67 (4.5%)
Pain	10/72 (13.9%)		5/67 (7.5%)
General disorders and administration site conditions - Other	1/72 (1.4%)		2/67 (3%)
Hepatobiliary disorders
Hepatobiliary disorders - Other	0/72 (0%)		1/67 (1.5%)
Immune system disorders
Allergic reaction	1/72 (1.4%)		1/67 (1.5%)
Infections and infestations
Bladder infection	0/72 (0%)		1/67 (1.5%)
Breast infection	1/72 (1.4%)		1/67 (1.5%)
Bronchial infection	1/72 (1.4%)		0/67 (0%)
Gum infection	0/72 (0%)		1/67 (1.5%)
Laryngitis	1/72 (1.4%)		0/67 (0%)
Otitis media	0/72 (0%)		1/67 (1.5%)
Papulopustular rash	1/72 (1.4%)		0/67 (0%)
Sinusitis	1/72 (1.4%)		0/67 (0%)
Upper respiratory infection	2/72 (2.8%)		1/67 (1.5%)
Upper respiratory infection	3/72 (4.2%)		1/67 (1.5%)
Urinary tract infection	1/72 (1.4%)		4/67 (6%)
Urinary tract infection	2/72 (2.8%)		4/67 (6%)
Vaginal infection	0/72 (0%)		1/67 (1.5%)
Infections and infestations - Other	3/72 (4.2%)		2/67 (3%)
Injury, poisoning and procedural complications
Bruising	1/72 (1.4%)		0/67 (0%)
Wound complication	1/72 (1.4%)		0/67 (0%)
Wrist fracture	1/72 (1.4%)		0/67 (0%)
Injury, poisoning and procedural complications - Other	0/72 (0%)		1/67 (1.5%)
Investigations
Alanine aminotransferase increased	16/72 (22.2%)		6/67 (9%)
Alkaline phosphatase increased	3/72 (4.2%)		10/67 (14.9%)
Aspartate aminotransferase increased	14/72 (19.4%)		8/67 (11.9%)
Blood bilirubin increased	2/72 (2.8%)		1/67 (1.5%)
Cardiac troponin T increased	0/72 (0%)		1/67 (1.5%)
CD4 lymphocytes decreased	0/72 (0%)		1/67 (1.5%)
Cholesterol high	9/72 (12.5%)		3/67 (4.5%)
Creatinine increased	1/72 (1.4%)		10/67 (14.9%)
Hemoglobin increased	1/72 (1.4%)		2/67 (3%)
Lymphocyte count decreased	6/72 (8.3%)		0/67 (0%)
Lymphocyte count increased	2/72 (2.8%)		0/67 (0%)
Neutrophil count decreased	24/72 (33.3%)		39/67 (58.2%)
Platelet count decreased	3/72 (4.2%)		16/67 (23.9%)
Weight gain	2/72 (2.8%)		1/67 (1.5%)
Weight loss	1/72 (1.4%)		0/67 (0%)
White blood cell decreased	25/72 (34.7%)		29/67 (43.3%)
Investigations - Other	2/72 (2.8%)		1/67 (1.5%)
Metabolism and nutrition disorders
Anorexia	2/72 (2.8%)		4/67 (6%)
Dehydration	0/72 (0%)		2/67 (3%)
Hypercalcemia	1/72 (1.4%)		0/67 (0%)
Hyperglycemia	12/72 (16.7%)		12/67 (17.9%)
Hyperkalemia	0/72 (0%)		2/67 (3%)
Hypermagnesemia	1/72 (1.4%)		1/67 (1.5%)
Hypernatremia	0/72 (0%)		1/67 (1.5%)
Hypertriglyceridemia	1/72 (1.4%)		0/67 (0%)
Hypoalbuminemia	7/72 (9.7%)		8/67 (11.9%)
Hypocalcemia	7/72 (9.7%)		7/67 (10.4%)
Hypoglycemia	2/72 (2.8%)		5/67 (7.5%)
Hypokalemia	1/72 (1.4%)		1/67 (1.5%)
Hypokalemia	1/72 (1.4%)		8/67 (11.9%)
Hypomagnesemia	5/72 (6.9%)		23/67 (34.3%)
Hyponatremia	6/72 (8.3%)		5/67 (7.5%)
Hypophosphatemia	6/72 (8.3%)		7/67 (10.4%)
Obesity	1/72 (1.4%)		1/67 (1.5%)
Obesity	2/72 (2.8%)		2/67 (3%)
Metabolism and nutrition disorders - Other,	1/72 (1.4%)		5/67 (7.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/72 (15.3%)		5/67 (7.5%)
Arthritis	3/72 (4.2%)		5/67 (7.5%)
Back pain	6/72 (8.3%)		13/67 (19.4%)
Bone pain	8/72 (11.1%)		1/67 (1.5%)
Chest wall pain	1/72 (1.4%)		2/67 (3%)
Generalized muscle weakness	0/72 (0%)		2/67 (3%)
Growth suppression	0/72 (0%)		1/67 (1.5%)
Joint range of motion decreased	0/72 (0%)		1/67 (1.5%)
Joint range of motion decreased cervical spine	0/72 (0%)		1/67 (1.5%)
Muscle weakness lower limb	1/72 (1.4%)		0/67 (0%)
Myalgia	13/72 (18.1%)		2/67 (3%)
Neck pain	4/72 (5.6%)		3/67 (4.5%)
Neck soft tissue necrosis	0/72 (0%)		1/67 (1.5%)
Osteoporosis	3/72 (4.2%)		1/67 (1.5%)
Pain in extremity	7/72 (9.7%)		1/67 (1.5%)
Musculoskeletal and connective tissue disorder - Other	5/72 (6.9%)		6/67 (9%)
Nervous system disorders
Akathisia	1/72 (1.4%)		0/67 (0%)
Dizziness	2/72 (2.8%)		9/67 (13.4%)
Dysgeusia	15/72 (20.8%)		11/67 (16.4%)
Encephalopathy	1/72 (1.4%)		0/67 (0%)
Headache	25/72 (34.7%)		18/67 (26.9%)
Hypersomnia	0/72 (0%)		1/67 (1.5%)
Memory impairment	1/72 (1.4%)		1/67 (1.5%)
Paresthesia	7/72 (9.7%)		1/67 (1.5%)
Peripheral motor neuropathy	11/72 (15.3%)		4/67 (6%)
Peripheral sensory neuropathy	40/72 (55.6%)		10/67 (14.9%)
Presyncope	0/72 (0%)		2/67 (3%)
Nervous system disorders - Other	2/72 (2.8%)		1/67 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	1/72 (1.4%)		0/67 (0%)
Psychiatric disorders
Agitation	1/72 (1.4%)		1/67 (1.5%)
Anxiety	24/72 (33.3%)		17/67 (25.4%)
Depression	14/72 (19.4%)		7/67 (10.4%)
Hallucinations	1/72 (1.4%)		0/67 (0%)
Insomnia	24/72 (33.3%)		15/67 (22.4%)
Libido decreased	0/72 (0%)		1/67 (1.5%)
Psychiatric disorders - Other	1/72 (1.4%)		1/67 (1.5%)
Renal and urinary disorders
Bladder spasm	1/72 (1.4%)		0/67 (0%)
Urinary frequency	0/72 (0%)		1/67 (1.5%)
Urinary incontinence	1/72 (1.4%)		1/67 (1.5%)
Surgical and medical procedures - Other	0/72 (0%)		1/67 (1.5%)
Reproductive system and breast disorders
Breast pain	12/72 (16.7%)		10/67 (14.9%)
Dysmenorrhea	0/72 (0%)		1/67 (1.5%)
Irregular menstruation	1/72 (1.4%)		0/67 (0%)
Vaginal inflammation	1/72 (1.4%)		0/67 (0%)
Vaginal pain	1/72 (1.4%)		0/67 (0%)
Menopause	1/72 (1.4%)		0/67 (0%)
Reproductive system and breast disorders - Other	2/72 (2.8%)		2/67 (3%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	4/72 (5.6%)		0/67 (0%)
Cough	3/72 (4.2%)		4/67 (6%)
Dyspnea	6/72 (8.3%)		2/67 (3%)
Epistaxis	12/72 (16.7%)		1/67 (1.5%)
Hiccups	0/72 (0%)		1/67 (1.5%)
Laryngeal inflammation	1/72 (1.4%)		1/67 (1.5%)
Nasal congestion	5/72 (6.9%)		4/67 (6%)
Postnasal drip	2/72 (2.8%)		3/67 (4.5%)
Productive cough	0/72 (0%)		1/67 (1.5%)
Sinus disorder	2/72 (2.8%)		0/67 (0%)
Sleep apnea	0/72 (0%)		3/67 (4.5%)
Sore throat	3/72 (4.2%)		0/67 (0%)
Tracheal fistula	0/72 (0%)		1/67 (1.5%)
Wheezing	1/72 (1.4%)		0/67 (0%)
Respiratory, thoracic and mediastinal disorders - Other	3/72 (4.2%)		3/67 (4.5%)
Acute kidney injury	0/72 (0%)		4/67 (6%)
Skin and subcutaneous tissue disorders
Alopecia	42/72 (58.3%)		1/67 (1.5%)
Dry skin	7/72 (9.7%)		1/67 (1.5%)
Hyperhidrosis	0/72 (0%)		2/67 (3%)
Nail discoloration	6/72 (8.3%)		2/67 (3%)
Pain of skin	0/72 (0%)		1/67 (1.5%)
Pruritus	7/72 (9.7%)		2/67 (3%)
Rash acneiform	14/72 (19.4%)		3/67 (4.5%)
Rash maculo-papular	8/72 (11.1%)		1/67 (1.5%)
Scalp pain	3/72 (4.2%)		0/67 (0%)
Skin and subcutaneous tissue disorders - Other	11/72 (15.3%)		3/67 (4.5%)
Vascular disorders
Flushing	2/72 (2.8%)		2/67 (3%)
Hot flashes	13/72 (18.1%)		8/67 (11.9%)
Hypertension	22/72 (30.6%)		19/67 (28.4%)
Hypotension	1/72 (1.4%)		1/67 (1.5%)
Lymphedema	1/72 (1.4%)		0/67 (0%)
Superficial thrombophlebitis	0/72 (0%)		2/67 (3%)
Vascular disorders - Other	0/72 (0%)		1/67 (1.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.