2. Adjuvant Therapy of Triple Negative Breast Cancer
Eric P. Winer, MD
Dana-Farber Cancer Institute
Boston, USA

3. Triple Negative Breast Cancer
Immunohistochemistry
High grade ductal ER
HER2 PR
ER and PR <1% nuclear with positive normal breast internal control
HER2 “negative” is 0 or 1+ staining or 2+ staining with negative FISH – usually HER2 is 0
Rarely lobular
High degree genomic instability
slide courtesy of Andrea Richardson, MD, PhD

4. Estimated Breast Cancer Deaths From Triple Negative Disease
10-11% Breast Luminal
4-5% Breast TN
Triple Negative BC, While
Only Accounting for 15% of All
Breast Cancer, Is Responsible
For Excess Mortality
Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study
O’Brien et al. CCR, 2010 4

5. Heterogeneity of TNBC Genomic instability common
Multiple subsets with varying targets
Basal-like 1
Basal-like 2
Immunomodulatory
Mesenchymal and mesenchymal / stem cell – (PI3K/mTOR pathway)
LAR – (androgen receptor signaling)
Lehmann et al, JCI 2011

6. Triple Negative Breast Cancer: Distinct Risk of Relapse
Over
Time
Dent, Clin Cancer Res 2007; Liedtke, JCO 2008; Lin, Cancer 2008

7. Site of 1st TNBC Recurrence in NCCN
Lin et al, ASCO 2009

8. What is Optimal ADJUVANT Therapy for STAGE II/III TNBC?

9. For over a 15 years, the use of anthracyclines
and taxanes have been a standard approach
for high risk triple negative disease

10. CALGB 9344: HER2+ and ER- Predicts AC-Paclitaxel Benefit
These curves represent disease free survival of the combined sets 1 and 2 by ER and by HER2, as assayed by immunohistochemistry with MAb cb11.
As you can see, patients who were ER negative benefited from paclitaxel,
RETURN
but that the benefit appears larger in HER2 positive than in HER2 negative patients, as shown on your left.
In contrast, in ER positive patients, while HER2 positive patients again appeared to benefit from paclitaxel, there is no apparent difference between the curves in those women who were ER Positive.
Evaluation of this 3 way interaction was highly exploratory, and we have not performed formal statistical analysis of this effect.
Hayes DF, et al. NEJM 2007

11. Swain SM et al. N Engl J Med 2010;362:2053-2065
A Sequential Antracycline-Taxane Combination is the Standard of Care for Moderate-Risk TNBC
NSABP-B30
AC-T vs AT x 4 vs TAC x 6
POSSIBLE REGIMENS
AC-paclitaxel (dose dense)
AC-weekly paclitaxel
AC-docetaxel (every 3 weeks)
FEC-docetaxel
Swain SM et al. N Engl J Med 2010;362:

12. Blum et al, ASCO 2016

13. ABC Trials
“The primary aim of the joint efficacy analysis was to determine if the nonanthracycline regimen (TC) was noninferior to the standard doxorubicin-containing regimens (TaxAC)”
Primary endpoint: invasive disease-free survival (IDFS)
Secondary endpoints:
Recurrence-free interval (local, regional, distant breast recurrence/death only)
DFS-DCIS (incorporates DCIS)
Overall survival
Toxicity
Stratification attempted via:
Pathologic nodal status (0, 1-3, 4-9, >10)
Hormone receptor status (ER and PR negative vs. ER or PR positive)
Trial
Blum JL et al JCO 2017

14. Blum JL et al JCO 2017

16. Additional Data and Secondary Endpoints
Recurrence-free interval:
Improved with TaxAC
HR 1.51, 95% CI , p<0.001
OS:
No significant difference to date (HR % CI , p = 0.60)
Blum JL et al JCO 2017

17. Stratification Variables
Blum JL et al JCO 2017

18. Invasive Disease Free Survival by ER and Nodal Status
Blum JL et al JCO 2017

19. Conclusions and Clinical Practice
TaxAC is preferable to TC, with caveats:
The absolute overall benefit appears to be small
Benefit appears to be more prominent in ER- tumors or ER+ tumors with +LN
In some subgroups, benefit is quite substantial
Additional follow-up time will be needed for this data to mature and for OS analysis

20. Should Stage Affect the Choice of of a Treatment Regimen?
What is the optimal treatment for small,
node negative TNBC tumors?

21. Outcome in National Comprehensive Cancer Network Distant Relapse Free Survival HR-HER2-
Vaz-Luis et al. JCO 2014;32:

22. Options for Stage 1 Disease
Chemotherapy treatment options for low risk disease:
1) simple regimen (AC, TC, CMF)
2) sequential anthracycline/taxane
Enthusiasm for Chemotherapy
Possible Regimens
Microinvasion only
Virtually none
---
T1a
Low to moderate
Simple
T1b
Moderate to high
T1c
High
Simple or selectively sequential approach

23. Is There a Role for Platinum Chemotherapy in the Neo/Adjuvant Management of Triple Negative Breast Cancer?

24. Randomized Trials of Preoperative Platinum Chemotherapy for TNBC
Sikov et al. JCO 2015;33:13-21; von Minckwitz et al. Lancet Oncology, May 2014

25. Does Addition of Preoperative Platinum Improve Survival Outcomes for TNBC?
GeparSixto 3Y DFS:
Improved with Carbo
CALGB Y EVS:
Not Improved with Carbo
Mixed results on survival benefits from preop platinum in TNBC
Achieving pCR is a good surrogate for long-term outcomes on a patient level
No evidence that pCR rates can be used as a surrogate for survival on a trial level to compare regimens in TNBC
Sikov et al. SABCS 2015; von Minckwitz et al. SABCS 2015

26. Is Carboplatin Ready for Primetime in Unselected TNBC in the Adjuvant or Neoadjuvant Setting?NO
Need definitive study showing improvement in DFS and/or OS
If platinum is ultimately used, should it be added to standard therapy or substituted for one or more drugs?
Are there triple negative subtypes that are particularly sensitive to platinum, ie biomarker driven?

27. Adjuvant Platinum?: NRG-BR003
Primary hypothesis: The addition of carboplatin to AC->T will improve IDFS
Secondary endpoints:
OS, BCFS, toxicity

28. EA1131 PI: Ingrid Mayer RANDOMIZE
Capecitabine 1000 mg/m2 D1-14 q3 weeks x 6
Stage II/III TNBC
At least 1 cm residual disease in breast after neoadjuvant Rx
Cisplatin 75 mg/m2 q3 weeks x 4 OR
Carboplatin AUC 6 q3 weeks x 4
Stratified by PAM50
basal vs. non-basal
Observation arm removed in Spring 2016

29. What About Platinum in Patients with Inherited BRCA Mutation?

30. Pathologic complete response = 61%
Preoperative Cisplatin As Preoperative Therapy in Patients With BRCA1 Mutations
107 patients with BRCA1 mutations
Stage I-III disease
Treatment:
Preoperative Cisplatin 75 mg/m2 q 3 weeks x 4
Mastectomy
Path CR defined as no invasive tumor in breast/nodes
Pathologic complete response = 61%
Byrski et al. Breast Cancer Research and Treatment 2014 and Arun et al, JCO 2011

31. TNT Trial: 1st Line Carboplatin vs Docetaxel in Metastatic TNBC
Tutt et al, SABCS 2014

32. TNT Trial: Docetaxel vs Carboplatin in TNBC: Influence of BRCA Mutation Status
Tutt et al, SABCS 2014

33. Do We Have Sufficient Data To Incorporate Platinum in Early Treatment of BRCA Associated TNBC?
May never have large, definitive trial
Mounting evidence in neoadjuvant and metastatic settings
Biology is consistent with clinical observations
Probably ready or close to it – ideally would like to see results of neoadjuvant INFORM trial
How do we do it? Add to standard? Substitute for one or more agents?

34. 12-258 INFORM: preop cisplatin vs AC for BRCA 1/2 carriers
Schema: Randomized Phase 2: 166 patients
Multicenter: primary endpoint: show 20% improvement in pCR with cisplatin over AC
Principal Investigators:
Nadine Tung and Judy Garber

35. Summary
In general, high risk TNBC should be treated with a sequential anthraycline/taxane regimen
Patients with stage I disease, who are at lower risk, can be comfortably managed with CMF, AC, or TC
A variety of new treatment approaches are under evaluation, including immunotherapy, PARP inhibitors, and platinum
TNBC remains a challenging area and one that is ripe for intensive translational and clinical research