2. Neoadjuvant Therapy for Triple Negative Breast Cancer
Steven J. Isakoff, MD, PhD
Dana-Farber Harvard Cancer Center/ Massachusetts General Hospital Cancer Center
August 19, 2017

3. TNBC Case What would you recommend for treatment?
46 year-old premenopausal woman
Presents with new palpable mass in R breast
Diagnostic mammogram: At the 11:00 position, 3 cm from the nipple, a 4.1 x 2.1 x 2.2 cm mass with irregular borders was seen
Ultrasound-guided core needle biopsy with clip placement was performed and revealed a triple negative, poorly differentiated (grade 3) infiltrating ductal carcinoma with LVI present
Bilateral breast MRI confirmed known mass, no other suspicious findings. All visible nodes appeared morphologically normal.
Genetic testing sent, BRCA1/2 negative
What would you recommend for treatment?

4. What is the role of neoadjuvant therapy in TNBC?
Old view:
For inoperable or locally advanced cancers to convert to operable
No proven benefit in long term outcome over adjuvant
Modern View:
Preferred Standard of Care for stage 2/3
Improve breast conservation rates and reduce extent of breast surgery
Reduce extent of axillary surgery
May allow risk stratification to guide adjuvant therapy selection
Novel therapy development
Provide prognostic information as surrogate for disease free survival
Future role?:
Allow risk stratification and de-escalation of therapy

5. Association of pCR with Event Free Survival in Triple Negative Breast Cancer
FDA Meta-analysis
Cortazar SABCS 2012

6. Ongoing Controversy: Platinum Agents
What is the role of platinum in neoadjuvant therapy for TNBC in 2017?

7. Cisplatin and Breast Cancer
Sledge reported 47% response rate in first line metastatic disease unselected for subtype
RR range 42-54% in older studies in first line therapy
RR 0-9% in previously treated unselected patients
Renewed interest in patients with triple negative breast cancer
Association of TNBC and BRCA1 7

8. Platinum for Neoadjuvant Therapy in Sporadic TNBC and BRCA1 Mutation Carriers
> 2cm, Stage II/ III
Research Core Biopsy
N=28
Cisplatin 75mg/m2 q3wks x 4 cycles
Assess Response Standard Adjuvant Therapy per MD
pCR 22%
Garber et al, SABCS 2006; Silver et al, JCO 2010

9. ALLIANCE/CALGB Study evaluating addition of Carboplatin and Bevacizumab in Neoadjuvant Tx for Triple Neg Breast Cancer
N=443
ER/PR/HER2-
Stage II-IIIB
Sikov J Clin Oncol :13-21

10. Carboplatin improves pCR
ALLIANCE/CALGB Study evaluating addition of Carboplatin and Bevacizumab in Neoadjuvant Tx for Triple Neg Breast Cancer
Carboplatin improves pCR
Sikov J Clin Oncol :13-21

11. CALGB 40603 – Event –free survival for carboplatin

12. GeparSixto Trial: Neoadjuvant carboplatin for Triple Negative Breast Cancer
315 pts
(~53% TNBC)
40% node pos

13. GeparSixto: Carboplatin improves pCR for Triple Negative Breast Cancer

14. pCR Rates by germline BRCA status and Carboplatin in TNBC
OR 0.94 ( )
P= 0.92
OR 2.14 ( )
P=.004
66.7%
65.4%
55.0%
36.4%
gBRCA are highly sensitive to chemotherapy
Platinum does not add benefit to gBRCA pCR
Von Minckwitz, Lancet Oncology, 2014; Hahnen, JAMA Onc, 2017

15. Disease-free Survival: Effect of Carboplatin in TNBC
Median DFS Follow-up = 35 months
von Minckwitz et al. SABCS 2015

16. TILs in TNBC associate with improved pCR with platinum in GeparSixto
Denkert C, JCO 2015

17. Role of Platinum in Neoadjuvant TNBC

18. TBCRC 030: Neoadjuvant Cisplatin vs Paclitaxel in TNBC
>1.5 cm
Cisplatin
75 mg/m2
q 3 wk x 4
Paclitaxel
80 mg/m2
q wk x 12
Tissue Collection
Surgery
Complete
Adjuvant
Chemotherapy
Stratification
LN + vs –
T1/2 vs T3/4
Primary objectives:
Compare pCR in platinum cohort with and without Homologous Recombination Deficiency (HRD high score or BRCA1/2+)
Compare pCR in paclitaxel cohort with and without Homologous Recombination Deficiency
PI: Erica Mayer, DFCI

19. Is cisplatin better than AC for preoperative therapy for BRCA carriers?
Randomized Phase II trial: Neoadjuvant Cisplatin vs AC in Women with Germline BRCA Mutations
N. Tung, PI

20. Schema: INFORM trial N=85 Eligibility: BRCA1/2 + HER2-neg T> 1.5 cm
Research
biopsy
Cisplatin
75 mg/m2 x 4
AC x 4
dd or q 21 days
Surgery
Adjuvant
Chemo
N=85
N=170 (90 enrolled)
Multicenter study
Primary aims:
pCR and Residual Cancer Burden (designed to show 20% improvement with cisplatin over AC)
Secondary aim: biomarkers of response

21. Does platinum improve long term outcome: Adjuvant Platinum Therapy

22. Should Platinum be Standard for Neoadjuvant Tx for TNBC?
My View: No, not routinely, not yet…..
No threshold margin of improved pCR is associated with improved outcomes.
Studies are underpowered for Event Free Survival and Overall Survival with inconsistent results
Addition of carboplatin significantly increases toxicities and cost
Need to better identify biomarkers to predict platinum sensitive disease (such as molecular subtype, Homologous Recombination Deficiency Assay – TBCBC030)
Definitive Phase 3 trial is needed – NRG BR003 comparing standard adjuvant chemotherapy +/- carboplatin
Standard combination chemotherapy remains the standard of care
In selected cases, adding platinum is reasonable for improved local control

23. Can we use pCR/RCB in TNBC to reduce treatment?
HYPOTHETICAL TRIAL
Carboplatin/
taxane
Surgery
x 4-6
cycles
No pCR/
RCB 2/3
Yes pCR/
RCB 0/1
Adriamycin/cytoxan x 4
No further therapy
Hypothetical design:
Non-inferiority trial
HR boundary 1.15

24. Prospective Registry Study of AC-T and Taxotere/Carbo x 6 and impact of pCR
Carboplatin/Docetaxel pathological response by gBRCA status
Comparison of Carboplatin/Docetaxel and ACT pCR#
All
Patients (n=49)
BRCA1/2
Wild type
(n=36)
BRCA
Mutation
(n=13)
pCR; n(%)
32 (65%)
22 (61%)
10 (77%)
p=0.50
RCB 0/1; n(%)
38 (78%)
27 (75%)
11 (85%)
p=0.70
p=0.036*
p=0.038*
Sharma, ASCO 2016

25. Management of Residual Disease After Neoadjuvant Therapy
Masuda et al. NEJM 2017; Lee, Toi et al. SABCS 2015

26. CREATE-X: Adjuvant Capecitabine for non-pCR
Masuda et al. NEJM 2017; Lee, Toi et al. SABCS 2015

27. Management of Residual Disease After Neoadjuvant Therapy
The US NCI felt the data from CreateX was so compelling it mandated a change in the design of Ecog1131 which was evaluating use of adjuvant platinum with residual disease to make capecitabine the comparator.

28. Novel therapies for neoadjuvant TNBC

29. I-SPY 2 TRIAL Schema: HER2- Signatures
Immunotherapy in Pre-operative breast cancer
I-SPY 2 TRIAL Schema: HER2- Signatures
Presented By Rita Nanda at 2017 ASCO Annual Meeting

30. Immunotherapy in Pre-operative breast cancer
Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN
Presented By Rita Nanda at 2017 ASCO Annual Meeting

31. Immunotherapy in Pre-operative breast cancer
Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN
Pembrolizumab graduated to phase 3 – the Keynote 522 study
Presented By Rita Nanda at 2017 ASCO Annual Meeting

32. The future: Targeting the Heterogeneity of TNBC

33. Heterogeneity in response to neoadjuvant chemotherapy
Masuda et al Clin Cancer Res; 19(19) October 1, 2013

34. Potentially Actionable Mutations in post-Neoadjuvant Chemotherapy with residual disease
Balko, Cancer Discovery 2014;4:

35. Neoadjuvant Therapy with Ipatasertib (AKT inhibitor) with paclitaxel
Schema: LOTUS study
Taxol weekly + Ipatasertib 400mg QD (3wk on/1wk off) R
1L mTNBC
STRATIFY:Adjuvant or neoadj (y/n), PTEN status (null vs h-score 1 to 150 vs >150)
n = 120
Taxol weekly + Placebo
Primary endpoint: PFS in ITT and PFS in PTEN low
Secondary endpoint: PFS in Dx+ (PTEN loss + PIK3CA mutants), OS, ORR
PI3K/AKT/PTEN Altered by NGS
Kim, Lancet Oncology 2017

36. Neoadjuvant Therapy with Ipatasertib (AKT inhibitor) with paclitaxel
Schema: FAIRLANE Study
Surgery
Taxol weekly + Ipatasertib 400mg QD (3wk on/1wk off) x 12 wks
Neoadjuvant
T>1.5 cm R
STRATIFY:PTEN status (null vs h-score 1 to 150 vs >150), node, size
n = 150
Taxol weekly + Placebo x 12 wks
Primary endpoint: pCR in ITT and PTEN low
Secondary endpoint: pCR in PTEN low/PIK3CA/AKT altered
FAIRLANE Completed Accrual Summer 2017
Results to be presented ASCO 2018
Phase 3 study underway in 1st metastatic TNBC (and ER+)

37. Summary and Take-Home Points
Platinum agents can increase pCR rates with neoadjuvant therapy:
But, long term benefit remains inconsistent and controversial
Significantly increases toxicity
In the absence of more data, should not be routinely used in the neoadjuvant setting, but in select cases may be reasonable.
Capecitabine may have a role after neoadjuvant therapy with significant residual disease
Exciting preliminary results with neoadjuvant immunotherapy added to chemotherapy, now being tested in phase 3 studies.
Molecular sub-classification may lead to targeted novel agents in TNBC.
Finally, given the lack of preferred therapies, clinical trial participation should always be considered.

38. TNBC Case What would you recommend for treatment?
46 year-old premenopausal woman
Presents with new palpable mass in R breast
Diagnostic mammogram: At the 11:00 position, 3 cm from the nipple, a 4.1 x 2.1 x 2.2 cm mass with irregular borders was seen
Ultrasound-guided core needle biopsy with clip placement was performed and revealed a triple negative, poorly differentiated (grade 3) infiltrating ductal carcinoma with LVI present
Bilateral breast MRI confirmed known mass, no other suspicious findings. All visible nodes appeared morphologically normal.
Genetic testing sent, BRCA1/2 negative
What would you recommend for treatment?
My recommendation: If no clinical trial, standard neoadjuvant therapy with AC-T, with possible adjuvant capecitabine if significant residual disease

39. Thank you
Acknowledgments
Eric Winer
Nadine Tung
Erica Mayer
Laura Spring