neoadjuvant chemotherapy in TNBC and BRCA mutated

1. Neoadjuvant
Chemotherapy??
Baha’ Sharaf
KHCC
Amman-Jordan

2. TableofContents
11-benefits of neoadjuvant
chemotherapy
2
2-neoadjuvant vs adjuvant
chemotherapy
5
Immunotherapy
4
Benefit of platinum
3
3-the preferred neoadjunt
6
Benefit of PARPi

3. 1
1-benefits of neoadjuvant chemotherapy
Introduction

4. Our Story
Locally Advanced
Inoperable Breast
Cancer
(Haagensen)
Palliative Care
● Neoadjuvant
Chemotherapy
Trials for all
Stage III Disease
Neoadjuvant
Chemotherapy in all
Stages to Allow Breast
Conserving Surgery
????????
1983 1988 1990 2022
● Anhracyclines for
Locally Advanced
Inoperable Breast
Cancer
● Response Rate
72%
● Mastectomy: 44%

5. 2neoadjuvant vs adjuvant chemotherapy

6. NSABP B-18 : neoadjuvant vs adjuvant AC*4
Operable breast cancer
AGE LESS THAN 50

7. 3
thepreferred neoadjuvant

8. NSABP Protocol B-27. Preoperative doxorubicin plus cyclophosphamide
followed by preoperative or postoperative docetaxel

9. PreoperativeChemotherapy:Updates of NationalSurgicalAdjuvant BreastandBowel
Project Protocols B-18andB-27

10. Efficacy of anthracycline/taxane-based neo-adjuvant chemotherapy
on triple-negative breast cancer in BRCA1/BRCA2 mutation carriers
retrospective analysis
53 patients including 46 BRCA1, 6 BRCA2, and 1 combined BRCA1 and BRCA2 mutation.
All patients had been diagnosed with triple-negative breast cancer (TNBC)
The pCR rate was 38.3% [95% CI, 26%-55%] among BRCA1 mutation carriers, and 66%
among the 6 BRCA2 mutation carriers.
DFS (P < .01) and OS (P < .01) were significantly better in the pCR group than the non-
pCR group
published: 19 September 2017

11. PCR

12. Pathological complete response andlong-term clinicalbenefit
inbreastcancer: theCTNeoBC pooledanalysis.
Cortazar P, et al Lancet. 2014 Jul 12;384(9938):164-72
12 trials
11 955 patients ypT0/is ypN0

13. theCTNeoBCpooledanalysis:
AssociationbetweenpCRandevent-freesurvival,bybreastcancersubtype

14. 4
Benefitofplatinum

16. RandomizedTrials of PreoperativePlatinumChemotherapyfor TNBC
Sikov et al. JCO 2015;33:13-21; von Minckwitz et al. Lancet Oncology, May 2014

17. 3 yearDFS
CALGB 40603 3Y EVS:
Not Improved with Carbo
Does Addition of Preoperative Platinum Improve
Survival Outcomes for TNBC?

18. WhatAboutPlatinumin
PatientswithInherited
BRCA Mutation?

19. Preoperative Cisplatin As Preoperative Therapy in
Patients With BRCA1 Mutations
cisplatin
chemotherapy at a
dose of 75 mg/m2
every 3 weeks for four
cycles
four cycles of
Adriamycin and
Cyclophosphami
de
A pCR was observed in 65 of the 107 patients (61 %).
Byrski et al. Breast Cancer Research and Treatment 2014 and Arun et al, JCO 2011

20. 12-258 INFORM: preop cisplatin vs AC for BRCA 1/2 carriers
Schema: Randomized Phase 2: 166 patients
Principal Investigators:
Nadine Tung and Judy Garber

22. ● Systemic review and meta analysis

23. (A) BRCA-mutated breast
cancer patients; (B) breast
cancer patients without
BRCA mutations

24. ● 2019
● 7 studies, 808 TNBC patients, among which 159 were BRCA mutated.
● PCR (93/159; 58.4%) in mutated TNBC VS (410/808; 50.7%) in Wild type
(OR 1.459 CI 95% [0.953–2.34] p = 0.082).
This meta-analysis shows that the addition of
platinum to chemotherapy regimens in the
neoadjuvant setting increases pCR rate in
BRCA – mutated as compared to wild-type
TNBC patients. However, this trend did not
achieve statistical significance

25. Platinum-BasedNeoadjuvant ChemotherapyforBreastCancerWithBRCAMutations: AMeta-Analysis:
11/2020
Chang-JunWang1† ,YingXu1†,YanLin1† ,Han-JiangZhu2,Yi-DongZhou1 ,FengMao1 ,Xiao-HuiZhang1,
XinHuang1 ,YingZhong1, QiangSun1*andCheng-GangLi 3,4*
(pCR) 43.4% (59/136) vs 33.9% (77/227)
(odds ratio [OR]: 1.340, 95% confidence interval [CI] =
0.677–2.653, p = 0.400)

27. Characteristics of studies included based on treatment regimens: cisplatin
in monotherapy (139) 53%

28. Characteristics of studies included based on treatment regimens: platin derivates
(cisplatin or carboplatin) and anthracycline with/without taxanes(133)66%

29. Characteristicsofstudies includedbased ontreatmentregimens: standardchemotherapyregimen (anthracycline,
cyclophosphamide,taxanes) andcarboplatin(53)PCR:62%

30. Characteristics of studies includedbasedontreatment regimens: carboplatinplus
taxanes(108)63%

31. Finding the Cure
Starts With Hope

32. 5immunotherapy

33. Should neoadjuvant pembrolizumab be used in gBRCA1m and/or gBRCA2m carriers with TNBC
who meet eligibility for Keynote 522 (ie, tumor size ≥ 2 cm or nodal involvement)?
KEYNOTE-522:NeoadjuvantPembrolizumab+CTFollowedbyAdjuvantPembrolizumabinTNBC
Schmid. SABCS 2021. Abstr GS1-01.
Pembrolizumab 200 mg IV Q3W
+ Chemotherapy*
(n = 784)
Placebo + Chemotherapy*
(n = 390)
Pembrolizumab 200 mg IV Q3W
(n = 588)
Placebo
(n = 331)
Neoadjuvant Phase
24 wk
Adjuvant Phase
27 wk
Surgery
2:1
Adult patients
with newly
diagnosed TNBC
(N = 1174)

34. Slide credit: clinicaloptions.com
48 51
51
48
HR (95% CI)
1.24 (0.69-2.23)
Pembro + CT
PBO + CT
n/N
29/40
18/26
Events, %
72.5
69.2
83.8%
75.7%
KEYNOTE-522 Exploratory Analysis:
EFS by RCB Category
EFS in RCB-1
Pusztai. ASCO 2022. Abstr 503. Reproduced with permission.
EFS in RCB-2 EFS in RCB-3
EFS in RCB-0
9
6
3
0 48 51
100
80
60
40
20
0
15
12 33
30
27
24
21
18 45
42
39
36
EFS
(%)
Mo
94.7%
92.6%
100
80
60
40
20
0
15
12
9
6
3
0 33
30
27
24
21
18 51
48
45
42
39
36
EFS
(%)
Mo
55.9%
HR (95% CI)
0.52 (0.32-0.82)
Pembro + CT
PBO + CT
n/N
37/145
35/79
Events, %
25.5
44.3
HR (95% CI)
0.70 (0.38-1.31)
Pembro + CT
PBO + CT
n/N
26/497
16/219
Events, %
5.2
7.3
26.2%
100
80
60
40
20
0
15
12
9
6
3
0 33
30
27
24
21
18 45
42
39
36
EFS
(%)
Mo
84.4%
100
80
60
40
20
0
15
12
9
6
3
0 33
30
27
24
21
18 45
42
39
36
EFS
(%)
Mo
34.6%
HR (95% CI)
0.92 (0.39-2.20)
Pembro + CT
PBO + CT
n/N
12/69
9/45
Events, %
17.4
20.0

35. PARPi
06
Monotherapy or combination

36. I-SPY

37. BRIGHTNESSTRIAL

38. PARTNER:Arandomized,phaseII/IIItrialtoevaluatethesafetyandefficacyoftheadditionof olaparibtoplatinum-based
neoadjuvantchemotherapyinpatientswithtriple-negativeand/orgermlineBRCA-mutatedbreastcancer.
● is a 3-stage open label randomised Phase II/III trial of neoadjuvant Carboplatin AUC5 with
weekly Paclitaxel 80mg/m2 (CP) +/- olaparib (O) 150mgBD for 12 days x 4 cycles, followed by
clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and/or gBRCA patients
are eligible for inclusion. Primary endpoints are defined by stage: Stage 1 - Safety, Stage2 -
Schedule selection, and Stage 3 - Efficacy (pCR rate)
● Combinations of olaparib with neoadjuvant CP chemotherapy showed an acceptable and
manageable toxicity profile. Although haematological events were the most common, they
did not exceed historical frequencies reported for standard chemotherapy regimens

39. PARPi
This single-arm pilot study (NCT03329937) evaluated neoadjuvant
niraparib antitumor activity and safety in patients
with localized HER2-negative, BRCA-mutated breast cancer.
Twenty-one patients received niraparib 200 mg once daily in
28-day cycles. After 2 cycles, tumor response (≥30% reduction from
baseline) by MRI was 90.5% and 40.0% (6 of 15) of
patients who received only niraparib (2–6 cycles) had pathological
complete response
19% recived 2
cycles
81% received
more than 2
cycles
15 patients (71.4%)
had TNBC and 6
patients (28.6%)
had (HR+) BC

40. NeoadjuvantTalazoparibforPatientsWithOperableBreastCancerWithaGermlineBRCA
PathogenicVariant
All pts had triple-negative BC
Evaluable population
(N=48)
Evaluable population
(N=48)
ITT population
(N=61)
pCR by ICR, n (%)
[95% CI]
22 (45.8) [32.0, 60.6] 30 (49.2) [36.7, 61.6]
RCB by ICR, n (%)
[95% CI]
RCB 0 22 (45.8) [30.0, 62.6] 30 (49.2) [34.0, 64.5]
RCB I 0 1 (1.6) [0.2, 12.1]
RCB II 15 (31.3) [18.0, 48.5] 17 (27.9) [16.1, 43.7]
RCB III 0 0
Missing 11 (22.9) [11.8, 39.8] 13 (21.3) [11.2, 36.7]
phase 2, non-randomized, single-arm, open-label study

41. CONCLUSIONS