1. Triple Negative Breast Cancer
4/17/2018

2. General Principles
Cancers that have ≤1% expression of ER/PR as determined by IHC and that are 0-1+ by IHC, or 2+ and FISH-negative
More aggressive, more common in pre-menopausal, African-American and associated with obesity
BRCA mutations seen in 20% patients
Staging and management guidelines are similar to other subtypes- ? More use of neo-adjuvant chemo
TNBC has worst OS compares to other phenotypes, risk of recurrence peaks ~ three years after diagnosis and declines rapidly thereafter

3. TNBC: Molecularly Heterogeneous
Name
Characteristic gene expression
“LAR”, luminal AR
AR, ER (no ER by IHC), prolactin, HER4 signal
“MES”, mesenchymal
Cell cycle, damage response, growth factor
“BLIS”, basal-like immunosuppressed
Basal-like, ↓T-, B-, NK-cell and cytokine pathways
“BLIA”, basal-like immune activated
Basal-like, ↑immunoregulatory pathways, STAT
Overlap with PAM50
Some overlap with “TNBCtype”
All characterized by basal, immune, and stromal signatures
Burstein MD et al. Clin Cancer Res 2015

4. Choosing neo-adjuvant vs adjuvant chemo
Tumor shrinkage
Down stage axilla
Efficacy of chemo (response adjusted approach)
Prognosticate- pCR
Research- tumor samples while on chemo to identify tumor and patient specific biomarkers correlating with response
Allows time for genetic testing and plan reconstruction

5. Chemotherapy
NCCN: Regimens recommended in adjuvant setting may be considered in the pre-operative setting.
Preferred regimens: ddAC  ddPac,
ddAC  weekly Pac TC
Other regimens: AC, EC, CMF, ACDoc/Pac, TAC, FEC or FAC followed by taxane
Platinums added to NACT for TNBC?

6. NSABP B-18 and NSABP B-27
B18: N = 1523 pts with operable cancer randomized to pre-operative AC x4 vs post-operative AC x4
B27: N = 2411 pts with operable cancer randomized to:
pre-op AC x4  Sx
pre-op ACx4  pre-op Doc x4  Sx
pre-op ACx4 Sx  post-op Doc x4
Fischer et al. J Clin Oncol 1997
Bear et al. J Clin Oncol 2006

7. OS, DFS and RFI for Protocol B-18 and B-27
*B-18: DFS and OS trend favoring NACT for women < 50 yrs
** B-18 & B-27: pCR patients had superior DFS and OS
Rastogi et al. JCO 2008;26:

8. Patients with pCR in group 2 (pre-op AC  Doc) versus groups 1 and 3
Pathologic tumor response at the time of surgery by treatment arm. *P < for testing percentage of patients with pathologic complete response in group 2 (after doxorubicin and cyclophosphamide [AC] plus docetaxel) versus groups 1 and 3 combined (after AC), adjusted for age, clinical tumor size, and clinical nodal status. DCIS, ductal carcinoma-in-situ.
Harry D. Bear et al. JCO 2006;24:

9. Survival by pCR in NSABP-B18 and NSABP-B27
Rastogi et al. JCO 2008;26:

10. Refining Taxane therapy: E1199
Phase III adjuvant trial with N-4950, node positive or high risk node negative patients
Treatment arms: AC x4 every 3 weeks followed by Pac x4 every 3 weeks (std arm)
Comparison arms: weekly Pac x 12,
weekly Doc x 12
Doc every 3 weeks x4
Sparano et al. N Engl J Med 2008

11. Sparano et al. N Engl J Med 2008
E1199: DFS curves
Sparano JA et al. N Engl J Med 2008;358:
Sparano et al. N Engl J Med 2008

12. E1199: OS curves Sparano et al. N Engl J Med 2008
Sparano JA et al. N Engl J Med 2008;358:
Sparano et al. N Engl J Med 2008

13. Effects of Paclitaxel and Docetaxel.
TE1199: Toxicity profile
Effects of Paclitaxel and Docetaxel.
Table 2 Toxic Effects of Paclitaxel and Docetaxel.
Sparano JA et al. N Engl J Med 2008;358:
Sparano et al. N Engl J Med 2008

14. Dose density in Adjuvant setting: CALGB- 9741
Treatment schema.
Citron et al. J Clin Oncol. 2003

15. (A) Disease-free survival by dose density; (B) overall survival by dose density
DFS was significantly prolonged for the dose-dense regimens compared with the every-3-weeks regimens (risk ratio [RR] = 0.74; P = .010).
OS was significantly prolonged in the dose-dense regimens (RR = 0.69; P = .013)
4yr-DFS was 82% vs 75% favoring dose dense regimen
This dose-density effect remained significant even after adjusting for number of positive nodes, tumor size, menopausal status, and ER status.
DFS was significantly prolonged for the dose-dense regimens (II and IV) compared with the every-3-weeks regimens (I and III; risk ratio [RR] = 0.74; P = .010). This dose-density effect remained statistically significant even after adjusting for number of positive nodes, tumor size, menopausal status, and tumor ER status.
Citron et al. J Clin Oncol. 2003

16. AC Vs TC: adjuvant trial
Jones SE et al. J Clin Oncol. 2006

17. AC vs TC: Results
Jones SE et al. J Clin Oncol. 2009

18. AC Vs TC: Toxicity TC (%) AC (%) Neutropenia 62 58 Asthenia 75 77
Edema 34 20
Infection 19
Stomatitis 33 45
Vomiting 14 42
Myalgia 16
Febrile neutropenia 5%
2.5%
Jones SE et al. J Clin Oncol. 2006

19. GBG 69 – GeparSepto: Pac Vs Nab-Pac
Untch et al. Lancet Oncology 2016

20. GBG 69 - GeparSepto 275 TNBC: 48% vs 26% (p= 0.00027)
HR 2.69 ( )
Neuropathy worse with nab-P
Gr 3+ 11% vs 3% (p<0.0001)
Any grade CIPN 86% vs 66%
D/c rate 17% vs 6%
No data on EFS and OS benefit
ypT0N0
Untch et al. Lancet Oncology 2016

21. Role of Neoadjuvant Platinum in TNBC: Randomized Trials
Primary end-point: pCR rates
Study No
Backbone Regimen
No Carbo
Carboplatin
GeparSixto*
315
Weekly paclitaxel + liposomal dox + bev
37%
53%
P= 0.05
C40603**
433
Sequential weekly paclitaxel – AC +/- bev
41%
54%
P=0.0029
Tamura et al 75
Sequential weekly pacl+/- Carb AUC5 - CEF
26%
62%
*4-yr DFS from Gepar-Sixto HR 0.56 (p= ) favoring carboplatin reported at ESMO 2017
**Patients who became BCS candidates with neoadjuvant therapy 57% versus 44% , p= NS
** 3 year EFS and OS 74% and 83% respectively (study was not powered to assess the
treatment effects on either of these endpoints
Von Minckwitz et al. Lancet Oncol 2014; Sikov et al. JCO 2015;
Tamura et al. ASCO 2014, Abstract 1107; Untch et al. ESMO 2017

22. ISPY-2: Adaptive randomization of Veliparib-carboplatin
Adaptive trial design:
- minimize the exposure of patients to inactive agents
- detect more active regimens sooner
Adding veliparib and carboplatin to standard therapy
improved outcome in triple-negative breast cancer.
Rugo et al. N Engl J Med. 2016

23. Estimated Rate of pCR with Veliparib–Carboplatin versus the Concurrent HER2-Negative Control.
Figure 2 Estimated Rate of Pathological Complete Response with Veliparib–Carboplatin versus the Concurrent HER2-Negative Control. Panel A shows the probability distribution for all patients with HER2-negative disease, Panel B the probability distribution for patients with hormone-receptor–negative and HER2-negative (triple-negative) disease, and Panel C the probability distribution for patients with hormone-receptor–positive and HER2-negative disease. The red curves represent patients treated with veliparib–carboplatin plus paclitaxel followed by doxorubicin–cyclophosphamide, and the blue curves represent concurrent controls. The corresponding 95% probability intervals (PIs) (represented by the arrows) are shown for each. The mean of each distribution is the estimated rate of pathological complete response.
Rugo HS et al. N Engl J Med 2016;375:23-34
Rugo et al. N Engl J Med. 2016

24. BrighTNess trial R Veliparib + Carboplatin + Paclitaxel  AC 2:1:1
Eligibility: N = 624
Neoadjuvant chemo for TNBC (stage II and III) R
Placebo + Carboplatin + Paclitaxel  AC
Placebo + Placebo+ Paclitaxel  AC
Administration of Cb and Pac was allowed extend over 16 weeks if needed, no reduction in number of paclitaxel doses administered but decreased dose density
No effect on completion of subsequent ACx4 due to upfront Cb+Pac
42% patients required a reduction in the dose of carboplatin from the starting dose of AUC 6
to AUC 5, and 17%required a second reduction to AUC 4
Loibl et al. Lancet Oncology, 2018

25. BrighTNess Trial: Results

26. BrighTNess Trial: AEs Pac + Cb + Vel Pac + Cb Pac alone
Side effect (percent)
Gr 1/2
Gr 3/4
Neutropenia 13 57 8 53 7 3
Anemia 36 25 41 17 11
Thrombocytopenia 37 31 6
Febrile neutropenia 2 1
Nausea 59 62 29
Stomatitis 20 9
Vomiting 19 28 5
Peripheral neuropathy 38
Ongoing analysis for event-free survival and overall survival is projected for 2019
Loibl et al. Lancet Oncology, 2018

27. ABC (Anthracycline in breast cancer) Trials Schema
Node+ or High Risk Node-neg (T1c allowed only if TNBC or high grade/high risk oncotype)
Stratification Variables: Number of + Nodes (0, 1-3, 4-9, 10+); Hormone Receptor (ER or PgR+, Both Negative)
ARM 1 TaxAC Options)
ARM 2 (TC)
TAC q 3 wk
AC q 2 wk
PTX q 2 wk A B
AC q 3 wk
PTX q 1 wk C D
TC q 3 wk
Arm 1 Options Per Study
USOR A only
NSABP B-46I/USOR A only
NSABP B-49 - investigator choice 1A-1D
Endocrine therapy for ER+ or PgR+ patients for minimum of 5 years
Primary aim - determine if IDFS with TC is non-inferior to TaxAC
(Inferiority pre-defined as Cox model HR of > 1.18)
Secondary aim: RFI, OS and toxicity
Blum et al. J Clin Oncol. 2017

28. ABC Trials: Invasive Disease Free Survival
100 80
4 yr 60
Treatment N Events IDFS
Alive and Inv. Disease-free (%)
TC %
Δ=2.5%
TaxAC % 40
HR=1.23, 95% CI ( ) P=0.04 20 1 2 3 4 5 6 7
Years from Randomization
Blum et al. J Clin Oncol. 2017

29. ABC Trials: Overall Survival
100 80 60
Treatment N Deaths at 4 yr
Alive and Inv. Disease-free (%)
TC %
Δ=0.3% 40
TaxAC %
HR = 1.08, 95% CI ( ) P = 0.60 20 1 2 3 4 5 6 7
Years from Randomization
Blum et al. J Clin Oncol. 2017

30. ABC Trials: IDFS by Hormone and Nodal Status
Exploratory Analysis
Pts
TaxAC TC
Events
4 yr IDFS
TaxAC TC
Delta
HR (95% CI)
ER/PgR (-) N-
2.5%
1.31 ( )
1-3 N+
10.9%
1.58 ( )
4+ N+ 40
11.0%
1.34 ( )
ER or PgR (+)
378
- 2.7%
0.69 ( )
2.0%
1.14 ( )
5.8%
1.46 ( )
Blum et al. J Clin Oncol. 2017

31. CREATE-X: Phase III Trial Design
Neoadjuvant chemotherapy involved at least 4 cycles of anthracycline or one of the following regimens:
FEC x 3  docetaxel x 3
FEC x 3  TC x 3
TC x 3  FEC x 3
TC x 4
Standard therapy included 5 years of endocrine therapy for HR-positive cancer, no further systemic treatment for HR-negative cancer and radiation therapy if indicated
Primary endpoint: DFS
Secondary endpoints : OS, safety
Patients with HER2-negative Stage I-IIIB breast cancer Age 20-74, ECOG PS of 0 or 1
Neoadjuvant chemotherapy
Surgery
No complete response on pathological assessment or a complete response with positive lymph nodes
Randomization
Capecitabine group: Standard therapy and capecitabine 1,250 mg/m2 twice a day on days q3wk x 6-8 cycles
Control group: Standard therapy
Masuda N et al. N Engl J Med 2017;376(22):

32. CREATE-X: Primary Endpoint DFS
DFS in Full Analysis Set
DFS in Patients with Triple-Negative Disease
Capecitabine n = 443
Capecitabine n = 139
Control n = 444
Probability of disease-free survival
Probability of disease-free survival
Control n = 147
Δ=14%
Hazard ratio for recurrence, second cancer or death, 0.70 p = 0.01
Hazard ratio for recurrence, second cancer or death, 0.58
p = 0.21
Years since randomization
Years since randomization
Median follow-up was 3.6 years. Interim efficacy analysis (at 2 y after enrollment completion) showed that the primary endpoint had been met, so the trial was terminated early
DFS rate among all patients: Capecitabine 82.8% vs control 73.9% at 3 years, 74.1% vs 67.6% at 5 years
DFS rate among patients with triple-negative disease: Capecitabine 69.8% vs control 56.1% at 5 years
Masuda N et al. N Engl J Med 2017;376(22):

33. CREATE-X: OS Median OS not reached in either arm
OS in Full Analysis Set
OS in Patients with Triple-Negative Disease
Capecitabine n = 443
Capecitabine n = 139
Control n = 444
Control n = 147
Probability of overall survival
Probability of overall survival
Hazard ratio for death, 0.59
p = 0.01
Hazard ratio for death, 0.52
Years since randomization
Years since randomization
Median OS not reached in either arm
OS rate among all patients: Capecitabine 94.0% vs control 88.9% at 3 years, 89.2% vs 83.6% at 5 years
OS rate among patients with triple-negative disease: Capecitabine 78.8% vs control 70.3% at 5 years
Masuda N et al. N Engl J Med 2017;376(22):

34. CREATE-X: Efficacy of Adjuvant Capecitabine
Outcome
Capecitabine
Control HR
p-value
Five-year DFS (ITT)
74.1%
67.6%
HR = 0.70
p = 0.01
TNBC
69.8%
56.1%
HR = 0.58
HR-positive
76.4%
73.4%
HR = 0.81
Five-year OS (ITT)
89.2%
83.6%
HR = 0.59
78.8%
70.3%
HR = 0.52
93.4%
90.0%
HR = 0.73
DFS = disease-free survival; TNBC = triple-negative breast cancer
Masuda N et al. N Engl J Med 2017;376:

35. Chemotherapy conclusions
Pre-op AC is equivalent to post-op AC
Addition of pre-op Doc to pre-op AC improves pCR which translates in to improved survival
Pac given every week is better than every 3 weeks in terms of DFS and OS but is associated with increased neurotoxicity
Dose density improves DFS and OS in breast cancer at no added toxicity
TC regimen is strictly studied in adjuvant setting and need to use caution before using it pre-operatively

36. Chemotherapy conclusions
Substitution of Pac with Abraxane is still premature till DFS and OS data is available
Addition of carboplatin may be considered in TNBC, particularly those with inadequate response to AC
Anthracyclines can be avoided in HR+ patients with negative/limited nodes (less than 4 nodes)
TNBC generally treated with ACT, particularly node positive disease
Patient with residual disease after NACT can be considered for adjuvant capecitabine for 6 months (patients had not received carboplatin)

37. Sequencing chemo in metastatic TNBC
Anthracyclines (Doxil)
Taxanes: nab-paclitaxel
Platinums
Eribulin
Capecitabine
Gemcitabine
Ixabepilone
Others- vinorelbine, oral cytoxan or etoposide
Parp inhibitors
Combinations
TNT trial: phase III Cb vs Doc- ORR =31% vs 36% ( BRCA mutated 68% vs 33%)
TBCRC009 Trial: phase II mTNBC with one prior Rx (70% with Adria and Tax) – Cis and Cb: ORR Cis 37% Cb 23#

38. TnAcity trial in mTNBC- Phase II
Nab-Pac + Carboplatin
1:1:1
N = 191
First line chemo for mTNBC R
Nab-Pac + Gemcitabine
Carboplatin + Gemcitabine
ORR (%)
PFS (months)
OS (months)
Nab-Cb 72
7.4
16.4
Nab-Gem 39
5.4 (HR 0.6, p=0.02)
12.1
Cb-Gem 44
6.0 (HR 0.61, p=0.03)
12.6
Yardley D, et al San Antonio Breast Cancer Symposium

39. Scalp cooling device
Nangia JR et al. San Antonio Breast Cancer Symposium 2016;Abstract S5-02.

40. Scalp-cooling device (Paxman Scalp Cooling System)
SCALP Trial Schema
Eligibility: Stage 1 or 2 BC (Neo)adjuvant chemotherapy with anthracycline or taxane
N = 182, 2:1 randomization
Exclusion criteria:
Migraines
Anemia
Hypothyroidism
Other uncontrolled medical conditions R
Scalp-cooling device  (Paxman Scalp Cooling System)
Control
Assessed for:
Alopecia
Quality of life
Device safety
Nangia J et al. JAMA 2017;317:

41. SCALP: Primary Outcome- Hair Preservation
Fisher’s exact test p <
Success
Failure
50.5% (40.7%, 60.4%)
0% (0%, 7.6%)
Cooling
Non-cooling
Nangia J et al. JAMA 2017;317:

42. SCALP: Adverse Device Effects
Cooling N = 101
Cycle 1 n = 101
Cycle 2 n = 84
Cycle 3 n = 66
Cycle 4 n = 62
Headache
11.9%
10.7%
1.5%
6.5%
Nausea 4%
2.4%
1.6%
Dizziness 3%
1.2% 0%
Chills 1%
Paresthesia
Pruritus
Sinus pain
Skin and subcutaneous
tissue disorders
Skin ulceration
Nangia J et al. JAMA 2017;317:

43. Patient-reported comfort scale
SCALP: Quality of Life
Patient-reported comfort scale
Comfort scale
Cooling N = 101
Cycle 1 n = 101
Cycle 2 n = 84
Cycle 3 n = 66
Cycle 4 n = 62
Very comfortable
11.9%
16.7%
14.5%
Reasonably comfortable
51.5%
39.3%
47%
50%
Comfortable
28.7%
26.2%
21.2%
24.2%
Uncomfortable
5.9%
13.1%
12.1%
9.7%
Very uncomfortable —
2.4%
Not assessed 2% 3%
1.6%
Quality-of-life assessments showed no difference
Nangia JR et al. San Antonio Breast Cancer Symposium 2016;Abstract S5-02.

44. Targeting AR in TNBC MDV3100-11 Background
Phase II study of bicalutamide in 26 patients with AR+ TNBC: CBR 19%, mPFS 12 weeks
Enzalutamide > bicalutamide in mCRPC
Endpoints:
1°:
2°:
PFS, OS etc
AR biomarker
MDV
AR+ mTNBC
Any prior Rx
Enzalutamide 160 mg/d po
165 screened patients
89 AR > 10%
75 evaluable
61% 1st /2nd line
Endpoint
CBR16
35% (24-46%)
CBR24
29% (20-41%) RR 8%
Median PFS
14 wks (8-19)
Traina et al. ASCO 2015 44

45. PREDICT AR− PREDICT AR+
Biomarker to predict sensitivity to Enzalutamide in TNBC: multigene RNA based assay 64
PREDICT AR− 8 16 24 32 40 52
Time (weeks)
PREDICT AR+
Total, n (%)
62 (53%)
56 (47%)
CBR16, %
(95% CI) n
11%
(5, 21)
n = 7
39%
(27, 53)
n = 22
CBR24, % 6%
(2, 16)
n = 4
36%
(24, 49)
n = 20
0–1 Prior Lines
2+ Prior Lines
Active
Confirmed RR
PREDICT AR+ 8 16 24 32 40 52 64
Time (weeks)
Parker JS et al. ASCO 2015

46. Response to single-agent anti-PD-L1/PD-1 in mTNBC
Atezolizumab mg/kg or 1200 mg
(n=115)
Pembrolizumab
(n=222) 30
26%
23% 20
ORR (%)
11% CR PR 10
4.6% 1L
2L+ (58%) 1L
2L+
KEYNOTE-086 Cohort B
KEYNOTE-086 Cohort A
1L, first line; 2L, second line; CR, complete response; ORR, objective response rate; PD-1, programmed death -1; PD-L1, programmed death-ligand 1; PR, partial response
Schmid, et al. AACR 2017; Adams, et al ASCO 2017

47. Durable responses with anti-PD-L1 mAb atezolizumab
Median OS 9.3 months
Median duration of response in responders 21 months
Higher RR associated with high TILs and PD-L1
100 80 60 40 20
-20
-40
-60
-80
-100
1 year
RECIST v1.1 response
PR/CR (n=11)
SD (n=15)
PD (n=66)
NE (n=1)
Discontinued
New lesion
>100%
irPR
2 years
Change in sum of largest diameters from baseline (%)
irPRa
irPR
irPRa
168
336
588
672
840
924 84
252
420
504
756
Time on study (days)
Phase Ia atezolizumab in mTNBC. aRe-treatment period not plotted. CR, complete response; irPR, PR per irRC; irRC, immune-related response criteria; NE, not evaluable; ORR, objective response rate; PR, partial response; PD, progressive disease; PD-L1, programmed death-ligand 1;  SD, stable disease
Schmid, et al. AACR 2017

48. OS by best response to anti-PD-1 pembrolizumab in 2L+ metTNBC
Median OS 8.9 months
PD-L1 status not associated with response
100%
64.6%
100%
89.6%
39.0%
Events/
pts, n
Median (95% CI)
CR or PR
0/8
Not reached (NR−NR) SD
6/35
Not reached (12.7−NR) PD
66/103
7.1 mo (6.3−8.8)
100 90 80 70 60
OS, % 50 40 30 20
CR/PR SD PD 10 2 4 6 8 9 10 12 14 16
No. at risk
Time, months
CR/PR 8 8 8 8 8 4 2 SD 35 35 35 33 29 16 7 1 PD
103 94 72 63 39 20 4 1
2L+ pembrolizumab
CR, complete response; NR, not reportable; OS, overall survival; PR, partial response; PD, progressive disease; PD-1, programmed death-1; SD, stable disease
Adams, et al ASCO 2017

49. Atezolizumab + nab-Paclitaxel in mTNBC: Phase Ib Trial
Nab-paclitaxel 125 mg/m2 weekly, 3 weeks on, one week off with atezolizumab 800 mg every 2 weeks;
32 evaluable patients; response independent of PD-L1+
Impassion 130: Phase III trial Nab-Pac +/- atezolizumab ongoing
Adams et al, J Clin Oncol 34, 2016 (suppl; abstr 1009)

50. Eribulin + anti-PD-1 (pembrolizumab) in mTNBC: Phase IB
Percentage change in total sum of target lesion diameters from baseline
Duration of treatment
All 1L
(n=17)
2L/3L (n=22)
PD-L1+
PD-L1− (n=18)
ORR
34.4%
41.2%
27.3%
29.4%
33.3%
CBR
40.6%
47.1%
36.4%
35.8%
44.4%
1L, first line; 2L/3L, second/third line; BOR, best overall response; CBR, clinical benefit rate; CR, complete response; IC, tumour-infiltrating immune cell; ORR, objective response rate; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PR, partial response; PD, progressive disease; SD, stable disease
Tolaney et al. SABCS 2016

51. Neoadjuvant chemotherapy + anti-PD-L1/anti-PD-1
KEYNOTE-173 phase 1/2 trial
Surgery
Chemotherapy + anti-PD-1
60%
90%
Cohort A (no platinum)
Cohort B (platinum)
Pathological CR =
ypT0 ypN0
Nab-Paclitaxel Q1W x12 ± carboplatin Q1W x12 + pembrolizumab Q3W x4  AC Q3W x4 + pembrolizumab Q3W x4
I-SPY 2 trial
Surgery
Chemotherapy +/- anti-PD-1
20%
60%
Control (no immunotherapy)
Immunotherapy (no platinum)
Pathological CR =
ypT0/is ypN0
Paclitaxel Q1W x12 + pembrolizumab Q3W x4  AC Q3W x4
AC, doxorubicin + cyclophosphamide; CR, complete response; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; Q1W, every week; Q3W, every 3 weeks; ypT0/Tis ypN0, no invasive residual in breast or nodes - noninvasive breast residuals allowed; ypT0 ypN0, no invasive or noninvasive residual in breast or nodes
Schmid, et al. ASCO 2017; Nanda, et al. ASCO 2017

52. its all about perspective…