1. Zoneddy Dayao, Rachel Rabinovitch, Stephen H. Dyar,
San Antonio Breast Cancer Symposium, December 6-10, 2016
NSABP B-52 (NRG Oncology) Evaluating Pathologic Complete Response Rates in Patients with Hormone Receptor-Positive, HER2-Positive Breast Cancer treated with Neoadjuvant Therapy of Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab (TCHP) with or without Concurrent Estrogen Deprivation Therapy
Mothaffar F. Rimawi, Reena S. Cecchini, Priya Rastogi, Charles E. Geyer, Jr, Louis Fehrenbacher, Philip J. Stella,
Zoneddy Dayao, Rachel Rabinovitch, Stephen H. Dyar,
Patrick J. Flynn, Luis Baez-Diaz, Soonmyung Paik, Sandra M. Swain, Eleftherios P. Mamounas, C. Kent Osborne, Norman Wolmark
Thank you. It is my privilege to present to you, on behalf of my colleagues, the primary analysis of NSABP B52 conducted by NRG Oncology

2. San Antonio Breast Cancer Symposium, December 6-10, 2016
Rationale
ER+/HER2+ tumors are less likely than ER-/HER2+ tumors to respond to dual anti-HER2 therapy.
ER may act as a pathway of resistance to anti-HER2 treatment.
Older trials suggested antagonistic effects of chemotherapy and endocrine therapy.
The rationale for our trial is based on the fact that ER+/HER2+ tumors are less likely than ER-/HER2+ tumors to respond to dual HER2 inhibition, and that ER may act as a pathway of resistance to anti-HER2 treatment.
Earlier trials that studied older chemotherapy agents combined with tamoxifen suggested antagonistic effects, but no data was available on combinations of more modern agents.
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3. San Antonio Breast Cancer Symposium, December 6-10, 2016
Hypothesis
We hypothesized that concurrent inhibition of ER and HER2, plus chemotherapy, will not be antagonistic, and will overcome resistance to treatment thus improving pCR rates in pts with ER+/HER2+ breast cancer.
We therefore hypothesized that concurrent inhibition of ER and HER2, plus chemotherapy, will not be antagonistic, and will overcome resistance to treatment thus improving pathCR rates in pts with ER+/HER2+ breast cancer.
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4. SABCS, December 6-10, 2016
NRG Oncology/NSABP B-52
HER2-Positive, ER and/or PgR-Positive Invasive Breast Cancer
Diagnosed by Core Needle Biopsy
REQUIRED BLOOD AND TISSUE
STRATIFICATION
RANDOMIZATION
Arm 1
TCH
every 21 days x 6 cycles +
Pertuzumab
Arm 2
TCH
every 21 days x 6 cycles +
Pertuzumab
Estrogen Deprivation
REQUIRED TISSUE
Core biopsy of primary tumor before Cycle 3 of TCHP*
*Obtained core biopsy in 103 pts.
NSABP B52 is a randomized trial for patients with histologically confirmed ER-positive, HER2-positive breast cancer. After undergoing study required blood and tissue collection, eligible patients were stratified according to their tumor size, nodal involvement, and menopausal status, and randomized to
Arm1: docetaxel, carboplatin, trastuzumab, and pertuzumab every 3 weeks, or
Arm2: with that same treatment plus endocrine therapy with estrogen deprivation. After receiving 6 cycles, patients proceeded to surgery and axillary staging.
SURGERY (lumpectomy or mastectomy) and axillary staging

5. San Antonio Breast Cancer Symposium, December 6-10, 2016
Eligibility Criteria
Invasive adenocarcinoma of the breast diagnosed by core needle biopsy
Clinical tumor ≥2.0 cm if clinically node negative. Any size if node positive.
Tumors must be hormone receptor positive and HER2+ by ASCO/CAP
The LVEF must be ≥50% regardless of the testing facility's lower limit of normal.
Adequate organ function
To be eligible, patients had to have:
Invasive adenocarcinoma of the breast diagnosed by core needle biopsy
Clinical tumor ≥2.0 cm if clinically node negative. Any size if node positive.
Tumors must be hormone receptor positive and HER2+ by ASCO/CAP
The LVEF must be ≥50% regardless of the testing facility's lower limit of normal.
And, adequate organ function.
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6. } ~ 8 yrs after start of trial
San Antonio Breast Cancer Symposium, December 6-10, 2016
Endpoints
Primary
pCR rate in the breast and nodes (ypT0-is ypN0)
Secondary
pCR rate in the breast
Clinical complete response
Toxicity
Recurrence-free interval OS
} ~ 8 yrs after start of trial
The primary endpoint for NSABP B52 is pathologic complete response rate in the breast and lymph nodes
Secondary endpoints included pathologic complete response in the breast, clincial complete response, and toxicity.
All patients will continue to be followed for the assessment of recurrence-free interval, overall survival, and second primary invasive cancer of any type. These analyses are expected to be performed about 8 years after the initiation of the trial, a period at which all patients should have been followed for at least 5 years.
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7. Statistical Considerations
San Antonio Breast Cancer Symposium, December 6-10, 2016
Statistical Considerations
The expected rate of pCR in the group not treated with estrogen deprivation is 45%.
Between January 2014 and February 2016, 315 patients were enrolled to provide 80% power to detect a 33% improvement, increasing the path CR rate from 45% to 60%.
Our statistical design assumed a pathCR rate of 45% in the control arm, not treated with estrogen deprivation.
Between January 2014 and February 2016, 315 patients were enrolled to provide 80% power to detect a 33% improvement, increasing the path CR rate from 45% to 60% with the addition of estrogen deprivation.
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8. NSABP B-52 Patient Characteristics*
San Antonio Breast Cancer Symposium, December 6-10, 2016
NSABP B-52 Patient Characteristics*
Age
≤ %
50 – %
≥ %
Race
White 79%
Black 12%
Other/Unk 9%
Tumor staging
cT0-cT2 74%
cT3-cT4c 24%
cT4d 2%
Clinical Nodal Status
Pos. 57%
Neg. 43%
* Patient characteristics were balanced between treatment regimens
Patient characteristics were balanced between treatment groups. 46% of the patients were under age 50%, 79% were Caucasian and 12% were African American. 26% of study participants had T3 or more advanced tumors and 57% had clinically node positive disease.
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9. NSABP B-52 Toxicity Toxicity TCHP (n=154) TCHP +Est Dep (n=157) Gr 0-1
San Antonio Breast Cancer Symposium, December 6-10, 2016
NSABP B-52 Toxicity
Toxicity
TCHP
(n=154)
TCHP +Est Dep
(n=157)
Gr 0-1
Gr 2
Gr 3
Gr 4
Diarrhea
42%
34%
23%
<1%
43%
35%
22% 0%
Nausea
60%
31% 9%
65%
29% 6%
Vomiting
82%
10% 8%
13% 5%
Dehydration
71%
20%
78%
17%
NSABP B52 enrolled the largest cohort treated with TCHP to date. TCHP has considerable toxicity with prominent GI toxicity like diarrhea, nausea, vomiting, and dehydration. There was no difference in toxicity between the two study arms.
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10. NSABP B-52 Toxicity Toxicity TCHP (n=154) TCHP +Est Dep (n=157) Gr 0-1
San Antonio Breast Cancer Symposium, December 6-10, 2016
NSABP B-52 Toxicity
Toxicity
TCHP
(n=154)
TCHP +Est Dep
(n=157)
Gr 0-1
Gr 2
Gr 3
Gr 4
Anemia
53%
35%
12% 0%
56%
26%
18%
Hypokalemia
83% 5%
10% 2%
80% 8% 1%
Febrile Neutropenia -
<1% 7%
Overall 3%
29%
59%
37%
52% 6%
Other toxicities are listed here. Anemia and hypokalemia were common. Febrile neutropenia occurred in 6% in the control arm and 8% in the experimental arm.
The overall rate of toxicity was quite high but not different in both study arms.
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11. NSABP B-52 pCR Breast and Nodes
San Antonio Breast Cancer Symposium, December 6-10, 2016
NSABP B-52 pCR Breast and Nodes
P=0.33
Now to efficacy results. NSABP B52 showed a pathologic complete response rate in the overall study population of 41% in the control arm and 46% in the experimental arm. This numeric increase was not statistically significant with a p-valuie of Subgroup analysis by menopausal status showed the path CR rate to be 44% vs 46% in premenopausal women and 38% vs. 45% in postmenopausal women, again with non-significant p-values or 0.80 and 0.33 respectively.
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12. San Antonio Breast Cancer Symposium, December 6-10, 2016
NSABP B-52 pCR Breast
P=0.51
I will now present secondary endpoint results
Pathologic complete response in the breast was 44% in the control arm and 47% in the experimental arm. This rate was 48% and 49% in premenopausal women, and 40% and 45% in postmenopausal women. All of these rates had no statistically significant differences.
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13. San Antonio Breast Cancer Symposium, December 6-10, 2016
Conclusion
The addition of estrogen deprivation to neoadjuvant chemotherapy was not antagonistic and did not increase toxicity.
The combination increased pCR rates numerically, but the improvement was not statistically significant.
Correlative science studies, evaluation of residual cancer burden (RCB), and long-term outcomes may help define the role of estrogen deprivation in the treatment of HER2+ early breast cancer.
In conclusion,
The addition of estrogen deprivation to neoadjuvant chemotherapy was not antagonistic and did not increase toxicity.
The combination increased pCR rates numerically, but the improvement was not statistically significant.
Correlative science studies, evaluation of residual cancer burden (RCB), and long-term outcomes may help define the role of estrogen deprivation in the treatment of HER2+ early breast cancer.
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14. San Antonio Breast Cancer Symposium, December 6-10, 2016
Conclusion
Given the toxicity of standard chemotherapy observed on this trial, findings from NSABP B52 argue for a tailored de-escalation approach where toxic treatments are omitted or replaced with less toxic ones without compromising outcomes.
And finally,
Given the toxicity of standard chemotherapy observed on this trial, findings from NSABP B52 argue for a tailored de-escalation approach where toxic treatments are omitted or replaced with less toxic ones without compromising outcomes.
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15. Acknowledgment Patients and their families
San Antonio Breast Cancer Symposium, December 6-10, 2016
Acknowledgment
Patients and their families
Co-authors and all participating NSABP investigators
NSABP staff at the Operation and Biostatistical Center
Collaborators from Baylor College of Medicine
Funding Sources: NCI and Genentech
I would like to acknowledge the patients who participated on this trial and their families, my co-authors, all participating NSABP investigators, NSABP staff at the operations and biostatistical center, my colleagues and collaborators at Baylor College of Medicine, the NCI and Genentech for funding the study, and all of you for your attention.
Thank you
This presentation is the intellectual property of the author. Contact at for permission to reprint and/or distribute.