E-Learning: The Neodjuvant Approach to Personalise Breast ...

THE NEOADJUVANT APPROACH TO PERSONALISE BREAST CANCER CARE

Valentina Guarneri, M.D., Ph.D

Department of Surgery, Oncology and Gastroenterology

University of Padova

Istituto Oncologico Veneto IRCCS, Padova, Italy

INTRODUCTION

Neoadjuvant therapy represents the use of systemic therapy as the first modality of treatment for a primary

malignant tumour

This strategy was first introduced into clinical practice in the‘70s for inoperable locally advanced breast cancer and

inflammatory breast cancer

The primary aim was to achieve operability for large, bulky tumours, often accompanied by matted involved

axillary nodes

In subsequent years, this strategy has been progressively used in patients candidates for mastectomy to increase the

chance for breast conserving surgery

Increases surgical options

◆ Operability of LABC

◆ BCS for mastectomy candidates

◆ SNB for N+ converted to N–

Affords similar survival outcomes compared with

adjuvant systemic therapy

Allows for in vivo evaluation of treatment sensitivity

NEOADJUVANT THERAPY:

A PLATFORM FOR PERSONALISED CARE

LABC: Locally Advanced Breast Cancer; BCS: Breast Conserving Surgery; SNB: Sentinel Node Biopsy

The higher rate of local recurrence is largely driven by trials allowing to avoid surgery in case of complete response

LONG-TERM OUTCOMES FOR NEOADJUVANT VS.

ADJUVANT CHEMOTHERAPY IN EARLY BREAST CANCER

Meta-analysis of individual patient data from ten randomised trials

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Lancet Oncol 2018;19(1):27–39. Reproduced under the terms of the Creative Commons CC-BY license Attribution 4.0 International (CC BY 4.0); available at: https://creativecommons.org/licenses/by/4.0/; accessed Nov 2020.

https://creativecommons.org/licenses/by/4.0/

NEOADJUVANT THERAPY IN THE CLINICAL PRACTICE

Neoadjuvant therapy is standard of care for the MAJORITY of stage IIB and stage III

Complete diagnostic workout, including cytology of suspicious axillary nodes and marker placement in primary

tumour should be performed before starting therapy, for proper surgical and radiotherapy planning

Anthracycline-taxane sequential chemotherapy for 6–8 courses is the standard backbone

Response is generally monitored with clinical examination, and breast imaging at the completion of the systemic

treatment plan

A multidisciplinary management is crucial


THE PROGNOSTIC VALUE OF pCR

pCR: pathologic complete response


THE PROGNOSTIC VALUE OF PCR

pCR: pathologic complete response. RD: residual disease

TN

pCR AND LONG-TERM OUTCOME:

THE CTNeoBC POOLED ANALYSIS

Cortazar P, et al; Lancet, 2014. Reprinted from The Lancet, 384(9938), Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis

164–72, copyright 2014, with permission from Elsevier.

HR+

HER2+ HER2+ HR+ HER2+ HR–

RESULTS FROM NEOADJUVANT TRIALS TO

ACCELERATE DRUG APPROVAL

Center for Drug Evaluation and Research, US FDA. July 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pathological-complete-response-

neoadjuvant-treatment-high-risk-early-stage-breast-cancer-use; accessed Nov 2020

Pathological Complete Response and Accelerated

Drug Approval in Early Breast Cancer Prowell TM, et al. N Engl J Med 2012;28;366(26):2438–41

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pathological-complete-response-neoadjuvant-treatment-high-risk-early-stage-breast-cancer-use

NEOADJUVANT STUDIES IN THE DIFFERENT

BC SUBTYPES

The HER2 positive subtype: a history of success

Triple negative breast cancer: opening a new era?

Luminal BC: reshaping the model

TARGETING HER2

The availability of anti-HER2 treatments has dramatically changed the prognosis of HER2+ breast cancer, in both

early and advanced disease setting

The role of trastuzumab in the adjuvant setting has been established by Phase 3 randomised trials

Early neoadjuvant trials reported substantial impact on pCR rate

ESCALATING STRATEGY IN HER2+ BC:

ADDING TRASTUZUMAB

The MDACC trial

Early termination of the study due to the strong advantage for trastuzumab-based combination

ER, estrogen receptor; FEC, fluorouracil, epirubicin, and cyclophosphamide;l; P, paclitaxel;; pCR, pathologic complete response; T, trastuzumab; Buzdar AU, et al. J Clin Oncol 2005;23(16):3676–5.

P-FEC

(n=19)

P-FEC + T

(n=23)

pCR 26.3% 65.2%

pCR ER+ 27% 61%

pCR ER– 25% 70%

pN0 78.9% 86.9%

ESCALATING STRATEGY IN HER2+ BC:

ADDING TRASTUZUMAB

The NOAH trial

bpCR, breast pathologic complete response; tpCR, total pathologic complete response (breast + axilla); OR, odds ratio.

Reprinted from The Lancet, 375(9712), Gianni L, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally

advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort, 377–84, Copyright 2010, with permission from Elsevier.

HER2+ disease

P-value

With

trastuzumab

(n=117)

Without

trastuzumab

(n=118)

bpCR 50 (43%) 26 (22%) 0.0007

tpCR 45 (38%) 23 (19%) 0.001

OR 102 (87%) 87 (74%) 0.009

ESCALATING STRATEGY IN HER2 + BC:

DUAL HER2 BLOCKADE

1. Baselga J, et al. Lancet 2012; 2. Guarneri V, et al. J Clin Oncol 2012; 3. von Minckwitz G, et al. Lancet Oncol 2014; 4. Robidoux A, et al. Lancet Oncol 2013; 5. Carey L, et al. ASCO 2013; 6. Hurvitz S, et al. SABCS 2013;

7. Gianni L, et al. Lancet Oncol 2012; 8. Schneeweiss A, et al. Ann Oncol 2013; 9. Untch M, et al. J Clin Oncol 2019; 10. Nitz UA, et al. Ann Oncol 2017; 11. Ramshorst MS, et al. Lancet 2018; 12. Guarneri V, et al. Ann

Oncol 2019; 13. Hurvitz SA, et al. Lancet 2017; 14. Bergh J, et al. ASCO 2019; 15. Press release.

CT + T + PCT + T CT + T + L TDMI + P TDMI

Pat

holo

gic

com

plet

e re

spon

se (

%)

0NeoALTTO1

20

40

80

100

60

Cher-

LOB2

Gepar63 NSABP

B-414

CALGB

406015

TRIO-

US6

NeoSphere7 Tryphaena8 Gepar79 WGS

ADAPT10

(HR–)

TRAIN-211 PerELISA12

(HR+ molecular

non-responders)

Kristine13 Predix14 I-SPY15

DUAL HER2 BLOCKADE: CT + TRASTUZUMAB-

LAPATINIB (NeoALTTO)

1. Reprinted from The Lancet, 379(9816), 2012; Baselga J, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial, 633-40, Copyright 2012, with

permission from Elsevier; 2. Reprinted from The Lancet, 15(10), 2014, De Azambuja E, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label,

multicentre, phase 3 trial and their association with pathological complete response, 1137–46 Copyright 2014, with permission from Elsevier.

Guarneri V., et al. J Clin Oncol, 30(16), 2012: 1989–95. Reprinted with permission. © 2012 American Society of Clinical Oncology;

Guarneri V, et al. Presented at ASCO 2020; abstract 582. Courtesy of Prof V Guarneri.

DUAL HER2 BLOCKADE: CT + TRASTUZUMAB-

LAPATINIB (Cher-LOB)

20

26

6

17

37

63

29 30

0

20

40

60

80

100

TH THP HP TP

pCR

, % ±

95%

CI

ER or PR positive

ER and PR negative

DUAL HER2 BLOCKADE:

TRASTUZUMAB + PERTUZUMAB

(NeoSphere)

Gianni L, et al. Lancet Oncol 2012;13(1):25–32

SURGERY

Patients with

operable or locally

advanced /

inflammatory*

HER2-positive BC

Chemo-naïve and

primary tumours

>2 cm (N=417)

TH (n=107)Docetaxel + trastuzumab

THP (n=107)Docetaxel + trastuzumab

+ pertuzumab

HP (n=107)Trastuzumab +

pertuzumab

TP (n=107)Docetaxel + pertuzumab

Study dosing: q3w x4

FEC q3w x3

Trastuzumab q3w cycles 5–17

FEC q3w x3

Trastuzumab q3w cycles 5-–17

Docetaxel q3w x4 →FEC q3w x 3

Trastuzumab q3w cycles 5-–17

FEC q3w x3

Trastuzumab q3w cycles 5–21

DUAL HER2 BLOCKADE:

TRASTUZUMAB + PERTUZUMAB

(NeoSphere)

Reprinted from The Lancet Oncol, 17(6), Gianni L, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere):

a multicentre, open-label, phase 2 randomised trial, 791–800, copyright 2016, with permission from Elsevier.

75% of the patients with operable breast cancer

72% HR+

18% neoadjuvant pertuzumab+trastuzumab

78% neoadjuvant anthracyclines

ESCALATING STRATEGY:

T-DM1 IN PATIENTS WITH RESIDUAL DISEASE

(KATHERINE)

von Minckwitz G, et al. N Engl J Med 2019;380:617–28; Geyer C, et al. Presented at SABCS 2018

Trastuzumab 6 mg/kg IV q3w,

14 cycles

RANDOMISE

1:1

T-DM1 3.6 mg/kg IV q3w,

14 cycles

• N=1486

• Centrally confirmed HER2-positive

breast cancer

• Residual invasive tumour in breast or

axillary nodes after PCT including: – Minimum of 6 cycles of CT

– Minimum of 9 weeks of T

From N Engl J Med, Minckwitz G, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer; 380:617–28, Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society; Geyer C, et al. Presented at SABCS 2018.

iDFS: ipsilateral invasive BC, locoregional relapse, contralateral invasive BC, distant relapse, death

ESCALATING STRATEGY:

T-DM1 IN PATIENTS WITH RESIDUAL DISEASE

(KATHERINE)

NeoSPHERE arm C: trastuzumab +

pertuzumab, no chemo2

TRAIN2: no anthracycline1 Kristine3

DE-ESCALATING STRATEGY

1. van Ramshorst MS, et al. Lancet Oncol 2018;19(12):1630–40; 2. Gianni L, et al. Lancet Oncol 2012;13(1):25–32; 3. Hurvitz S, et al. Lancet Oncol 2018;19(1):115–26

20

26

6

17

37

63

29 30

0

20

40

60

80

100

TH THP HP TP

pCR

(% ±

95%

CI)

ER or PR positive

ER and PR negative

67 68

0

20

40

60

80

100

FEC-T+Ptz PTC+Ptz

pCR

rate

(yp

TO

/is, y

pN0)

141/212 140/206

p=NS

Pat

ient

s w

ith a

pat

holo

gica

l

com

plet

e re

spon

se (

%)

0

20

40

80

100

60

Docetaxel,

carboplatin, and

trastuzumab

plus pertuzumab

Trastuzumab

emtansine

plus pertuzumab

Difference: –11.3 percentage points

(95% CI: –20.5 to –2.0)

Stratified two-sided p=0.016*

56

44

PAMELA trial:

HER2-enriched subtype as a predictor of pCR following

trastuzumab and lapatinib without chemotherapy1

PerELISA trial:

trastuzumab+pertuzumab + letrozole in patients with

HER2+/HR+ disease selected on the basis of Ki67

response after 2 weeks of letrozole2,3

pCR rate in molecular responders according to PAM50

DE-ESCALATING STRATEGY:

ROLE OF PATIENT SELECTION

1. Reprinted from The Lancet Oncol, 18 (4), Llombart-CussacA. et al. HER2-enriched subtype as a predictor of pathological

complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer

(PAMELA): an open-label, single-group, multicentre, phase 2 trial, 545–54, copyright 2017, with permission from Elsevier.

2. Guarneri V, et al. Presented at ASCO 2018; abstract 507. Figure provided courtesy of Prof V

Guarneri;

3. Guraneri V, et al. Ann Oncol 2019;30(6):921–26.

Distribution of

intrinsic molecular

subtypes at baseline

pCR at time of surgery,

by intrinsic molecular

subtype assessed at

baseline

THE HER2 POSITIVE SUBTYPE:

A HISTORY OF SUCCESS

Dual HER2 blockade significantly increases the chance of achieving a pCR, and is standard for high-risk patients

(reimbursement issues in EU)

KATHERINE trial demonstrates a clinically meaningful advantage of T-DM1 in patients with residual disease after

trastuzumab based neoadjuvant therapy

Effect of T-DM1 is consistent in pertuzumab-trastuzumab pretreated patients

De-escalating strategy (giving less initial treatment, with ‘’rescue‘’ postoperative treatment to suboptimal responders)

is attractive, aiming for personalised therapy


BC SUBTYPES


Triple negative breast cancer: opening a new era?


TRIPLE NEGATIVE BREAST CANCER

Triple negative breast cancer (TNBC) is the most lethal form of breast cancer

TNBC is more frequently diagnosed in younger women

Higher risk of earlier relapse

High risk for visceral involvement (CNS and lung)

Median survival from time of metastases rarely exceeds 18 months

Highly chemosensitive, with patients achieving pCR having similar outcome compared with the other BC subtypes

AIMING AT IMPROVING THE pCR RATE:

INTRODUCING PLATINUM SALTS AND BEVACIZUMAB

1. Huober J, et al. Breast Cancer Res Treat 2010; 2. Earl HM, et al. Lancet Oncol 2014; 3. von Minckwitz G, et al. N Engl J Med 2012; 4. von Minckwitz G, et al. Lancet Oncol 2014; 5. Sikov WM, et al. J Clin Oncol 2015;

6. Guarneri V, et al. Ann Surg Oncol 2015; 7. Gluz O, et al. SABCS 2015; 8. Untch M, et al. Lancet Oncol 2016; 9. Loibl S, et al. Lancet Oncol 2018.

0

10

20

30

40

50

60

TAC

Gepar31

EC-D

+Bev

PM PM+Cb

(+ Bev)

Gepar64

P-AC P+Cb-AC

(+/– Bev)

CALGB406035

P+Cb+bev

Ca.Pa.Be6

nabP-EC

Gepar78

EC-P

(+/– gem)

NeoTango2

nabP-Cb

ADAPT7

P+Cb

+Vel-AC

Brightness9

Pat

holo

gic

com

plet

e re

spon

se (

%)

EC-D

Gepar53

P+Cb-AC

P-AC

PLATINUM-BASED NEOADJUVANT CHEMOTHERAPY

IN TNBC

(Systematic review and meta-analysis)

Poggio F, et al, Ann Oncol 2018;29(7):1497–508

Effect of platinum on pCR irrespective

of BRCA status

No impact on event-free survival,

but BrighTNess data pending

Increased G3/4 haematological AEs

ROLE FOR BEVACIZUMAB IN EARLY TNBC?

Despite interesting preclinical background, no convincing evidence for a clinical impact of adding bevacizumab to

current chemotherapy standards

In the CALGB 40603 neoadjuvant trial, bevacizumab was associated with a non-significant pCR increase over

CT alone

In the GEPAR5 trial, bevacizumab produced a significant pCR increase in HER2– BC, with the effect mainly driven

by the TN cohort. No impact on survival reported

In the NSABP B-40 trial, a non-significant pCR increase was observed in HER2– disease, with the effect driven by

the HR+ cohort

The BEATRICE adjuvant trial reported no impact on DFS for bevacizumab plus standard chemotherapy over

standard chemotherapy alone

Sikov WM, et al. J Clin Oncol 2014;33:13–21; von Minckwitz G, et al. Ann Oncol 2014;25:2363-72; von Minckwitz G, et al. N Engl J Med 2012;366(4):299–309;

Miklos GL. N Engl J Med 2012;366(17):1638; Cameron D, et al. Lancet Oncol 2013;14(10):933-42.

0

10

20

30

40

50

60

ITT

CTc+

Placebo

CTc+

Pembro

PD-L1+

CTc+

Placebo

CTc+

Pembro

CTd CTd+

Atezo

CTd CTd+

Atezo

ITT PD-L1+

PBO

+CTb

Durva

+CTb

ITT PD-L1+

CTa CTa+

Pembro

I-SPY-21

PBO

+CTb

Durva

+CTb

NeoTRIPaPDL14GEPARNuevo2 KEYNOTE 5223

CTe CTe+

Atezo

CTeCTe+

Atezo

ITT PD-L1+i

IMPASSION0315

57.6%

41.1%

68.8%

49.3%

PD-L1+(TC or IC IHC SP263 ≥1%): 87% PD-L1+(CPS IHC 22C3 ≥1): 83% PD-L1+(IC IHC SP142 >0): 56%

70

20%*

60%*

68.9%

54.9%

51.2%

64.8%

53.4%

44.2%

58%

50.7%

40.8%

43.5%

48%

51.9%

PD-L1+(IC IHC SP142 >0): 47%

AIMING AT IMPROVING THE pCR RATE:

IMMUNE-CHECKPOINT INHIBITORS

*Estimated probabilities of pCR. a. Pac → DC; b. Nab-Pac → EC(dd); c. Carboplatin+Pac → EC/DC; d. Carboplatin+Nab-Pac (anthra given after surgery); e. Nab-Pac → DC(dd)1. Nanda R, et al. JAMA Oncol 2020; 2. Loibl S, et al. Ann Oncol 2019; 3. Schmid P, et al. NEJM 2020; 4. Gianni L, SABCS 2019; 6. Harbeck N, et al. ESMO 2020.

CHEMOTHERAPY +/– PEMBROLIZUMAB:

KEYNOTE 522

a. carboplatin (at a dose based on area under the concentration–time curve of 5 mg/mL/min q3w or 1.5 mg/mL/min qw in the first 12 weeks; c. Paclitaxel 80 mg per square meter of

body-surface area once weekly); c. doxorubicin 60 mg/m2; d. epirubicin 90 mg/m2; e. cyclophosphamide 600 mg/m2 q3w.Schmid P, et al. N Engl J Med 2020;382:810–21

Placebo

Key eligibility criteria

Age ≥18 years

Newly diagnosed TNBC of

either T1c N1-2 or T2-4 N0-2

ECOG PS 0-1

Tissue sample for PD-L1

assessment

Stratification factors:

Nodal status (+ vs –)

Tumour size (T1/T2 vs T3/T4)

Carboplatin schedule

(qw vs q3w)

RANDOMISE

2:1

Carboplatina +

paclitaxelbDoxoc/epirubicind +

cyclophosphamidee

Pembrolizumab 200 mg q3w

Carboplatina +

paclitaxelbDoxoc/epirubicind +

cyclophosphamidee

SURGERY

Placebo

Pembrolizumab

200 mg q3w

Neoadjuvant phase Adjuvant phase

Neoadjuvant Treatment 1

(cycles 1–4; 12 weeks)

Neoadjuvant Treatment 2


Adjuvant Treatment


KEYNOTE 522:

BASELINE CHARACTERISTICS AND pCR

IA1-Interim Analysis 1

IA1: Primary pCR analysis to test primary hypothesis of pCR based on prespecified first 602

subjects (pre-calculated P-value boundary for significance of 0.003)

IA2: If pCR hypothesis successful at IA1 (thus definitive), pCR will not be formally tested at IA2

a. PD-L1 combined positive score defined as number of PD-L1–positive cells (tumour cells, lymphocytes, and macrophages) divided by

total number of tumour cells x 100. PD-L1 positivity was defined as CPS ≥1.Schmid P, et al. N Engl J Med 2020;382:810–21

Characteristic, n (%) All subjects, N=602

Pembro + Chemo

n=401

Placebo + Chemo

n=201

Age, median (range), yrs 49 (22–80) 48 (24–79)

ECOG PS 1 73 (18.2) 28 (13.9)

PD-L1-positivea 334 (83.3) 164 (81.6)

Carboplatin schedule

q1w

q3w

167 (41.6)

234 (58.4)

83 (41.3)

118 (58.7)

Tumour size

T1/T2

T3/T4

296 (73.8)

105 (26.2)

148 (73.6)

53 (26.4)

Nodal involvement

Positive

Negative

208 (51.9)

193 (48.1)

104 (51.7)

97 (48.3)Pembro +

Chemo

Placebo +

Chemo

KEYNOTE 522:

PCR BY PD-L1 STATUS

By PD-L1 status: ypT0/Tis ypN0

Schmid P, et al. N Engl J Med 2020;382:810–21

pCR

(%,

95%

CI)

KEYNOTE 522:

EVENT-FREE SURVIVAL

IA2-Interim Analysis 2

From N Engl J Med, Schmid P, et al. Pembrolizumab for Early Triple-Negative Breast Cancer, 382, 810–21. Copyright ©2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

◆ EFS at IA2 (first interim of EFS): precalculated P-value boundary for significance of 0.000051 (HR <0.4)

◆ Prespecified analysis plan allows alpha passing from successful endpoint(s) to other(s)

1174 patients randomised 2:1

from Mar 17 to Sep 18

IMPASSION 031:

STUDY DESIGN

National Library of Medicine (U.S.). Identifier NCT03474458. Available at: https://clinicaltrials.gov/ct2/show/NCT03197935?term=impassion031&draw=2&rank=1. Accessed 30 October 2020;

Mittendorf EM, et al. Lancet 2020 ;396(10257):1090–100.

Primary end point: pCR

Secondary: pCR in PD-1 selected subgroups, EFS, OS, safety, PROs

Nab-paclitaxel 125

mg/m2 IV qw +

Placebo

for 12 weeks

RANDOMISE

1:1

Nab-paclitaxel 125

mg/m2 IV qw +

atezolizumab 840 mg

IV q2w

for 12 weeks

Patients with previously

untreated Stage II/III TNBC

N=204

Stratification:

Stage II vs III at diagnosis

PD-L1 Ico vs IC1/2/3

Doxorubicin 60 mg/m2 IV q2w +

cyclophosphamide 600 mg/m2 IV

q2w +

Placebo

for 8 weeks

Doxorubicin 60 mg/m2 IV q2w +

cyclophosphamide 600 mg/m2 IV

q2w +

atezolizumab 840 mg IV q2w

for 8 weeks

SURGERYpCR

evaluation

Atezolizumab

1200 mg IV

q3w

for 11 doses

Monitoring

Survival

follow-up

Unblinded adjuvant or monitoring phase

https://clinicaltrials.gov/ct2/show/NCT03197935?term=impassion031&draw=2&rank=1

57.6

41.1

0

20

40

60

80

100

Atezolizumab-chemo Placebo-chemo

pCR

(95%

CI)

%

95/165 69/168

IMPASSION031: CO-PRIMARY ENDPOINT pCR (ITT)

a. One-sided significance boundary P=0.0184 (accounting for the adaptive enrichment design). P=0.0085 for the intersection hypothesis of pCR in the ITT and PD-L1–positive population.

Δ16.5% (5.9, 27.1)

P=0.0044a


IMPASSION031: CO-PRIMARY ENDPOINT pCR IN PD-L1

POSITIVE TUMOURSa

aPD-L1+, PD-L1 IC ≥1%; PD−L1−, PD-L1 IC <1%. bOne-sided significance boundary P = 0.0184 (accounting for the adaptive enrichment design).

P=0.0085 for the intersection hypothesis of pCR in the ITT and PD-L1–positive population.

68.8

49.3

0

20

40

60

80

100


pCR

(95%

CI)

%

53/77 37/75

Δ 19.5% (4.2, 34.8)

P=0.021b

47.7

34.4

0

20

40

60

80

100


pCR

(95%

CI)

%

42/88 32/93

Δ 13.3% (–0.9, 27.5)

pCR (95% CI), ypT0/is ypN0 (PD-L1–positive) pCR (95% CI), ypT0/is ypN0 (PD-L1–negative)

Did not cross significance

boundary of 0.0184


ADJUVANT CAPECITABINE IN PATIENTS WITH

RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY

CREATE-X trial

Masuda N, et al. N Engl J Med 2017;376(22):2147–59.

Capecitabine 2500 mg/mq/day 1–14

6–8 cycles + Standard

RANDOMISE

(n=900)

Control: Standard

Stratification factors:

ER, age, NAC, ypN,

5FU and institution

Standard therapy:

HR+: Hormone therapy

HR–: No further systemic treatment

Pathology non-

pCR or node +SurgeryNAC

HER2-

CREATE-X TRIAL:

DFS AND OS (ITT AND TNBC)

Possible pharmacogenomic effect of

fluoropirimidine in Asian population?

Capecitabine use in adjuvant setting

is off-label

From N Engl J Med 2017, Masuda N, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy, 376:2147–59. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

Balanced for adjuvant and

post-neoadjuvant patients

A-BRAVE TRIAL

EudraCT: 2016-000189-45. Available at: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-000189-45; accessed 30 October 2020.

Observation

RANDOMISE

1:1

Avelumab for 1 year

Co-primary endpoints:

1. DFS in all-comers;

2. DFS post-neoadjuvant stratum

Secondary endpoints:

OS, Safety, Biomarkers

High-risk primary TNBC patients who

completed treatment with curative

intent including surgery, chemotherapy

and radiotherapy (if indicated)

Stratum A: Adjuvant

Stratum B: Post-neoadjuvant

https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-000189-45

TRIPLE NEGATIVE BREAST CANCER:

OPENING A NEW ERA?

Sequential anthra-taxanes remains standard for the majority of the patients.

Adding carboplatin to A-T as neoadjuvant therapy increases the rate of pCR independently of BRCA status.

Because of higher risk of haematologic toxicity and lack of OS advantage, the addition of platinum salts remains

an option

For patients with residual disease after neoadjuvant chemotherapy: consider capecitabine (CREATE-X) and or

clinical trials

Immunotherapy improves pCR rate (and EFS in Keynote522), but additive side effects (early and late)


BC SUBTYPES


Triple-negative breast cancer: opening a new era?


HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE BC

The pCR rate after neoadjuvant chemotherapy is consistently lower in patients with HR+ disease

Tumour biology is the driver of treatment selection, and most patients with HR+/HER2– disease are offered adjuvant

hormonal therapy alone, even in case of node-positive disease

For several years, neoadjuvant hormonal therapy has been traditionally limited to elderly, unfit patients with large,

inoperable disease

New scenario with AIs, alone or as a backbone to targeted agents

RANDOMISED TRIALS OF CHEMOTHERAPY VS.

ENDOCRINE THERAPY

Neoadjuvant hormone therapy vs. neoadjuvant cytotoxic

chemotherapy

Spring LM, et al. JAMA Oncol 2016;2(11):1477–86.

Clinical response

Breast-Conserving Surgery

pCR

Source OR (95% CI)

Alba, et al. 2012 2.11 (0.92, 4.82)

Palmieri, et al. 2014 0.34 (0.06, 1.98)

Semiglazov, et al. 2007 0.93 (0.55, 1.57)

Total 1.08 (0.50, 2.35)

Alba, et al. 2012 0.68 (0.30, 1.54)

Semiglazov, et al. 2007 0.63 (0.36, 1.11)

Total 0.65 (0.41, 1.03)

Favors chemotherapyFavors endocrine

0.01 0.1 1.0 10 100

0.01 0.1 1.0 10 100

0.01 0.1 1.0 10 100

OR (95% CI)

Alba, et al. 2012 3.13 (0.12, 78.77)

Palmieri, et al. 2014 Not estimable

Semiglazov, et al. 2007 1.84 (0.53, 6.47)

Total 1.99 (0.62, 6.39)

Heterogeneity: Χ2=0.09 (P=0.76), I2=0%

Test for overall effect: z=1.16 (P=0.25)

2



2



2

• Prognostic value of pCR appears weaker in HR+HER2– BC than HER2+ and TN BC

• Need for alternative markers

5-year OS p

pCR

No pCR

79.7%

91.1% 0.002

ER-, pCR

ER-, no pCR

67.4%

83.9% <0.0001

ER+, pCR

ER-, no PCR

84.5%

96.4% 0.04

PROGNOSTIC VALUE OF pCR IN HR+/HER2– BC

1. Guarneri V, et al. J Clin Oncol 2006;24(7):1037–44; 2. Reprinted from The Lancet 384 (9938), Cortazar P, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled

analysis, 164–72, copyright 2014, with permission from Elsevier.

Prognostic value of pCR after primary

chemotherapy in relation to hormone

receptor status and other factors1

pCR and long-term clinical benefit in breast cancer:

the CTNeoBC pooled analysis

POETIC TRIAL: PERIOPERATIVE AI TREATMENT AND

PREDICTION OF LONG-TERM OUTCOMES IN EARLY BC

Robertson J, et al. Presente at SABCS 2017; abstract GS1-03. By permission of Prof J. Robertson

TTR by baseline and 2-week Ki67

Patients with low Ki67 after 2 weeks

of pre-operative endocrine therapy

experienced superior event-free survival

Time post randomisation (years)

PREOPERATIVE ENDOCRINE PROGNOSTIC INDEX

PEPI score

Validated algorithm, PEPI score combines anatomical and

biological data at surgery after preoperative endocrine therapy

Ellis MJ, et al. J Natl Cancer Inst, 2008, 100(19), 1380–8, by permission of Oxford University Press.

RFS BCSS

HR Points HR Points

Pathologic T1/2 - 0 - 0

Pathologic T3/4 2.8 3 4.4 3

Node Negative - 0 - 0

Node Positive 3.2 3 3.9 3

Ki 67 0%-2.7% (0-1) - 0 - 0

Ki 67 >2.7%-7.3% (1-2) 1.3 1 1.4 1

Ki 67 >7.3%-19.7% (2-3) 1.7 1 2.0 2

Ki 67 >19.7%-53.1% (3-4) 2.2 2 2.7 3

Ki 67 >53.1% (>4) 2.9 3 3.8 3

ER Allred 0-2 2.8 3 7.0 3

ER Allred 3-8 - 0 - 0

RFS and BCSS by PEPI groups

Group 1: score 0; group 2: score 1-3; group 3: score>3

Clinical response (WHO criteria)

E L A

ORR (ITT) 62.9% 74.8% 69.1%

CR 21.8% 21.3% 17.9%

PR 41.1% 53.5% 51.2%

No change 22.6% 15.7% 16.3%

Disease

progression6.5% 4.7% 7.3%

Surgical indication before

neoadjuvant therapy

Surgery

performed

Marginal for BCS (n=189) BCS 83%

Mastectomy 17%

Mastectomy (n=159) BCS 51%

Mastectomy 49%

Inoperable (n=4) BCS 75%

Mastectomy 25%

Surgical procedures performed after neoadjuvant AI

by baseline surgical feasibility

PHASE 2 NEOADJUVANT COMPARISON BETWEEN

LETROZOLE, ANSTROZOLE AND EXEMESTANE

ACOSOG Z1031

ORR: Objective Response Rate; CR: Complete Response; PR: Partial Response; BCS: Breast Conserving Surgery

Ellis MJ, et al.J Clin Oncol 2011;29(17):2342–9.

Luminal A Luminal B

Paradoxical Ki67 increase


LETROZOLE, ANASTROZOLE AND EXEMESTANE

ACOSOG Z1031

Ellis MJ, et al. J Clin Oncol, 29(17), 2011: 2342–9. Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved.

PEPI 0

ypT1/2N0

Ki67 2.7%

ER Allred 3–8

Adjuvant chemotherapy was administered in 18 (15.1%) of 119 PEPI 0 cases and 162 (47.5%) of 341 PEPI non-0 cases


LETROZOLE, ANSTROZOLE AND EXEMESTANE

ACOSOG Z1031

Ellis MJ, et al. J Clin Oncol 2017;35(10):1061–9a; Reproduced under the Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/; accessed 30 Octoer 2020.

https://creativecommons.org/licenses/by-nc-nd/4.0/

ALTERNATE: STUDY DESIGN

Ma CX, et al. Presented at ASCO 2020; abstract 504.

Eligible patients

Postmenopausal

cT2-T4c, anyN, M0

ER pos (Allred 6-8)

HER2– BC

RANDOMISE

Arm I

Anastrozole (ANA)

Adjuvant phaseNeoadjuvant

Arm II

Fulvestrant (FULV)

ET x 24 weeks

Arm III

ANA + FULV

SURGERYmPEPI

0

No adj

chemo

Arm I

ANA x4.5 years

Arm II

FULV x1.5 years → ANA x3 years

Arm III

(ANA + FULV) x1.5 years

→ ANA x 3 years

FOLLOW-UP

ET x4.5 years

mPEPI

Non-0

Adj chemo

PTCET of physician’s choice

FOLLOW-UP

10 years from

surgery

Neoadjuvant chemo

groupSURGERY

Adjuvant therapy of physician’s

treatment choice (PTC)

Ki67 >10%

Week 4 or 12

Degree of Ki67 suppression similar among treatments

Fewer than 2% of the patients progressed while on endocrine therapy, maybe because of the Ki67 triage strategy

Survival data awaited

ALTERNATE PRIMARY ENDPOINT RESULT

Endocrine-sensitive disease rate (ESRD) = mPEPI0+pCR

Ma CX, et al. Presented at ASCO 2020; abstract 504.

ANA

n=434

FULV

n=431

ANA + FULV

n=434

mPEPI = 0, n (%) 77 (17.7) 94 (21.8) 87 (20.0)

pCR, n (%) 4 (0.9) 4 (0.9) 2 (0.5)

ESDR, n (%)

(97.5% CI)

81 (18.6)

(14.6, 23.2)

98 (22.7)

(18.4, 27.6)

89 (20.5)

(16.3, 25.2)

Fisher’s Exact Test P-value

compared to ANA arm0.15 0.55

Trials Arms Patients, n Main outcomes

NeoPalAna Pal+Ana (+/-LHRh) 50 87% complete cell cycle arrest

NeoMONARCH Abema+Ana

Abema

Ana

223 Higher Ki 67 decrease for combo

PALLET Let

Palbo+Let


FELINE Let-ribo (intermittent)

Let-ribo (continuous)

Let-placebo

120 No difference in PEPI score 0, clinical and pathological

response, higher Ki67 decrease for combo at D14 not

maintained at surgery

NeoPAL Let + Palbo

Chemotherapy

53

53

Similar RCB, High Ki67 reduction for let-palbo

CORALLEEN Let + Ribociclib

Chemotherapy

49

52

Similar rates of ROR-low disease at surgery pCR 5.8% with

CT vs 0 with let-R, PEPI score 0 17 % with Ct and 22% with

Let-R

NEOADJUVANT TRIALS OF HT+CDK4/6I IN

HR+/HER2– BC

Ma, et al. Clin Cancer Res 2017; Arnedos, et al. Ann Oncol 2018; Hurvitz, et al. Clin Cancer Res 2020; Johnston, et al. J Clin Oncol 2018; Khan, et al. ASCO 2020; Cottu, et al. Ann Oncol 2018;

Prat, et al. Lancet Oncol 2020.

Trials Arms Patients, n Main outcomes

NeoPalAna Pal+Ana (+/-LHRh) 50 87% complete cell cycle arrest

NeoMONARCH Abema+Ana

Abema

Ana


PALLET Let

Palbo+Let


FELINE Let-ribo (intermittent)

Let-ribo (continuous)

Let-placebo

120 No difference in PEPI score 0, clinical and pathological

response, higher Ki67 decrease for combo at D14 not

maintained at surgery

NeoPAL Let + Palbo

Chemotherapy

53

53

Similar RCB, High Ki67 reduction for let-palbo

CORALLEEN Let + Ribociclib

Chemotherapy

49

52

Similar rates of ROR-low disease at surgery pCR 5.8% with

CT vs 0 with let-R, PEPI score 0 17 % with Ct and 22% with

Let-R

LUMINAL BC:

RESHAPING THE MODEL

Endocrine therapy is a valuable option to allow for breast conservative surgery in HR+/HER2– patients

Primary endocrine therapy does not jeopardise local disease control

Endocrine therapy needs prolonged treatment to exert its maximum therapeutic benefit; however, early markers of

benefit are available (Ki67, PEPI score) and might allow for a more personalised treatment

Neoadjuvant endocrine therapy is the ideal backbone to test new agents

Needs for additional data to confirm Ki67 as an early marker of benefit after endocrine therapy + CDK4/6i

“less-than-pCR” doesn’t

necessarily mean poor outcome

pCR doesn’t guarantee cure

OPTIMISING THE MODEL

Let’s dig a little deeper: pCR vs. no pCR may be too simplistic

HETEROGENEITY OF “LESS THAN pCR”

Residual cancer burden validation

HER2+ HR+/HER2–TNBC

Symmans WF, et al. J Clin Oncol, 35(10), 2017: 1049–60. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

Combined Nodal status and post neoadjuvant

chemotherapy Ki671

Tumour Infiltrating lLymphocites (TILs) in TNBC with

residual disease post neoadjuvant chemotherapy2

HETEROGENEITY OF “LESS THAN pCR”

1. Guarneri V, et al. Ann Oncol 2008;20(7):1193-8; 2. Dieci MV, et al. Ann Oncol 2014; ;25(3):611–8.

Time (years)

Loss of HER2 amplification after trastuzumab-

based neoadjuvant therapy1

Rate of HER2 loss according to neoadjuvant trastuzumab

exposure and outcome2

HETEROGENEITY OF ”LESS THAN pCR”: HER2 LOSS

;2. Guarneri V, et al.. ASCO 2012; Ann Oncol 2013 1. Reprinted) from Clin Cancer Res, 2009, 15 (23), 7381–8, Mittendorf EA, et

al. Loss of HER2 Amplification Following Trastuzumab-Based Neoadjuvant

Systemic Therapy and Survival Outcomes, with permission from AACR.

OPTIMISING THE MODEL: PLATFORM TO RANK

STRATEGIES TO BE TESTED IN THE ADJUVANT SETTING

Lesson learned from NeoSphere and NeoALLTO

1. Gianni L, et al. Lancet Oncol 2012;13(1):25-32; 2. From N Engl J Med 2017, von Minckwitz G, et al. Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer 377:122-131, Copyright © (2017) Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society.; 3. Reprinted from The Lancet, 379(9816), 2012; Baselga J, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial, 633-

640, Copyright 2012, with permission from Elsevier; 4. Piccart-Gebhart M, et al. J Clin Oncol 34(10), 2016: 1034–42. Reprinted with permission. © 2016 American Society of Clinical Oncology. All rights reserved.

OPTIMISING THE MODEL

Trial-level correlation between treatment effect on pCR and EFS/OS

Reprinted from The Lancet, 384(9938), Cortazar P, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. 164–72 copyright 2014, with permission from Elsevier.

Consider the dilution effect of post-surgery treatments

Event-free survival Overall survival

CONCLUSIONS

Neoadjuvant therapy has a clear role in the management of BC

pCR at single patient level has an established prognostic value

Triage of new agents is faster and cheaper

To better identify pCR patients eligible for de-escalated systemic treatment, future research should be more focused

on factors associated with distant events and on predictors of both pCR and EFS

Post-neoadjuvant studies allow for a rational clinical positioning of new agents

Post-neoadjuvant strategy taking into account the biology of residual disease might further improve the cure rate

THANK YOU!

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