ERKEN EVRE TRIPLE NEGATİF MEME KANSERİNDE TEDAVİ YÖNETİMİ

(1)

ERKEN EVRE TRIPLE NEGATİF MEME KANSERİNDE TEDAVİ YÖNETİMİ

Dr. Saadettin KILIÇKAP (LİV Hospital-Tıbbi Onkoloji Bölümü) Dr. İlknur KEPENEKÇİ BAYRAM (AÜTF, Genel Cerrahi ABD) Dr. Güler YAVAŞ (Ankara Başkent Ün. Radyasyon Onkolojisi)

Dr. Gamze DURHAN (Hacettepe Ünv. Radyoloji ABD

(2)

Olgu; 34y, K, Premenopozal

Ocak 2018

• 1 yıl önce sol memede ele gelen sertlik

• Özg: - İlaç:- Sigara: 1-2 adet/g/15 yıl

• Soyg: Hala meme ca 55y, diğer hala 45y meme ca,

Teyze 45y meme ca, diğer teyze over ca?

(3)

Olgu; Meme Görüntüleme

• Meme US (Ocak 2018):

• Sol meme saat 1 de EB 4 cm hipoekoik nodüler lezyonlar

• sol meme saat 12 de 13 mm düzensiz sınırlı heterojen solid lezyon

• sağ meme de EB 9 mm hipoekoik nodüler lezyonlar,

• aksiller LAP yok

• MG (Mart 2018): sol meme ADK’da çevre parankimle örtülü yüksek yoğunluklu 55 mm nodüler lezyon

(4)

Soru 1. Bu Hastada Evrelemede Hangisi Önerilmez ?

1. Hemogram- Biyokimya 2. Toraks- Batın BT

3. TVKS

4. Meme MR 5. Beyin MR 6. PET-BT

(5)

(6)

(7)

Olgu; Meme MR (Mart 2018)

Sol meme saat 5’de yüksek olasılıklı malign lezyon

(8)

Olgu; PETBT

• Sol meme primer kitle

• Sol internal mammarian LN ve inferior LN

• Sol retropektoral

• Sol aksiller kitlede

• uterin kavite ve bilateral adneksde artmış FDG

(9)

Olgu; Patoloji

• Sol meme kitlesinden bx-Sol aksiler LN İİAB (9.3.18)

• Pat: IDK, gr3, ER +, PR-, HER2-,

Aksiler LN İİAB: Polimorfik lenfoid populasyon

• Patoloji Kons: Tripl Negatif, ki67 %60

(10)

Olgu Özet

• 34y K

• Aile öyküsü++

• cT3N0M0 TNMK

BRCA 1 Heterozigot mutant****

(11)

NSABP B 18

T1-3 N0-1 M0

S + adjuvan AC vs preop AC + S

(12)

(13)

Metaanalysis of Randomized Trials Comparing Pre vs.

Postoperative Systemic Chemotherapy (N= 9 trials, 3046 patients)

Mauri et al. JNCI 2005; 97: 188-194 (PMID: 15687361)13

(14)

1. Hangi Hastaya ?

2. Amaç ne ? Patolojik tam yanıt vs operabilite

Sorular ?

(15)

Neoadjuvant Kemoterapi için Aday Hastalar

• Klinik inoperable – Klinik Evre IIIB-C

• Evre IIIB/  - T4a (göğüs duvarı), (cilt), c (ikisi), d (inflamatuar)

• Evre IIIC – herhangi N3 hastalık, ipsilateral infraklavikular (N3a), internal mammary (N3b), veya supraklaviküler (N3c) hastalık

• Operable –Lokal ileri – Klinik Evre IIB-IIIA

• T3 - tumor > 5 cm

• N2a- palpable lenf nodu -fikse

• N2b – internal mammary nodes (no axillary nodes)

• Operable, adjuvant Kemoterapi Endike Olan – Klinik Evre IIA-IIIA

• T2 veya N1 hastalık

• TNBC veya HER2-pozitif meme kanseri

• Genetik Testi endikasyonu olanlar - hereditary breast/ovarian ca (HBOC)

15

(16)

Neoadjuvant Kemoterapi için Lehte ve Aleyhte Görüşler

• Lehte

• Yüksek Klinik Yanıt Oranı

• Evrenin gerilemesi –meme ve lenf nodlarında

• MKC oranını artırması

• Aksiller diseksiyondan koruması

• Farmakodinamik biyomarkerlar - prognostik

• ypT0N0/minimal residual hastalık – Düşük nüks oranı

• Tam Yanıtlı olmayan hastalar – Ek sistemik tedavi

• Genetik test için zaman sağlayarak lokal cerrahi tedaviye yön verebilir

• Aleyhte

• Hastalık progresyonu riski

• Toksisiteye bağlı tedavi cerrahinin gecikmesi

• Yüksek yanlış negative SLN biyopsi pranı

• Nüks ve Sağkalım avantajı yok, lokal nüks oranları biraz yüksek (MKC ise) (randomized trials)

(17)

Medikal Onkolog Olarak Çekincelerimiz ?

(18)

EEMK-NAT ÇEKİNCELERİ

• NAT sırasında gelişecek PD ?

• Overtreatment ?

• Kaybolan Tm nedeniyle MKC yapamamak

• NAT sonrası rezidü hastalık ?

• NAT sonrası yanıtlı hastada CS sorunu?

• Klinik ve radyolojik N0 hastaların hepsi pN0 ?

• cN(+) tüm hastalarda NAT ?

• ypN0 dönen hastalarda SLNB esnasındaki FNR oranları (%10)

• Aksiller klip? Seed? ≥3 SLNB?

(19)

1. Hangi Hastaya ?

2. Amaç ne ? Patolojik tam yanıt vs operabilite 3. Neoadjuvan KT sonrası

a) Hangi cerrahi; MKC vs MRM

b) Hangi Lenf Nodu Yönetimi; SLNÖ vs ALND 4. Patolojik yanıt elde edilemeyen hastada tedavi ?

Sorular ?

(20)

Patolojik Alt-tipler & pCR

Cortozar Lancet 2014

(21)

Patolojik Tam Yanıt Uzun Sağkalım ile İlişkili

12 çalışma n=11 955 hasta

(22)

CTNeoBC Meta-analysis

12 randomized neoadjuvant trials including 12,993 patients

1. Is pCR associated with long term outcomes (EFS, OS) ?

• Yes- individual patients with pCR have improved EFS and OS

2. Which pCR definition is best associated with long term outcome?

• Use consistent definition – ypN0 plus ypT0/is or ypT0

3. Which subtype does pCR associated with long term outcomes?

• Aggressive subytpes, including TNBC (EFS HR 0.24, p<0.001), HR+, grade 3 (HR 0.27, p<0.001), and HER2+ (HR 0.39, p<0.001)

4. What magnitude of pCR improvement in a randomized trial will predict long term clinical benefit (EFS and OS improvement)?

• Could not be established possibly due to:

• low pCR rates

• heterogeneous population

• lack of targeted therapies (except NOAH trial)

• Larger pCR differences between treatment arms are needed to translate into long-term outcome and may vary according to breast cancer subtype

Cortazar et al. SABCS 2012, Lancet 2014 (PMID: 24529560)22

(23)

Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage:

Individual patient-level meta-analyses of over 27,000 patients

Results: EFS and OS in Overall Population

5-year EFS pCR vs RD: 88% vs 67%

5-year OS pCR vs RD: 94% vs 75%

Overall Survival

Event Free Survival

Blue: pCR group

Orange: Residual disease (RD) group

Spring LM, et al. SABCS 2018

TNBC HER2+ HR+/HER2-

5-year EFS pCR vs

RD: 90% vs 57% 5-year EFS pCR vs RD: 86% vs 63%

5-year EFS pCR vs RD: 97% vs 88%

Results: EFS and OS by Subtype

Blue: pCR group

Orange: Residual disease (RD) group

Event Free Survival Event Free Survival Event Free Survival

Results: Adjuvant Chemotherapy

Blue: pCR without adjuvant chemotherapy Orange: pCR with adjuvant chemotherapy

5-year EFS in patients with pCR followed by adjuvant chemotherapy: 86%;

pCR without additional adjuvant chemotherapy: 88%

pCR was associated with significantly improved EFS in both groups, and there

was no significant difference in Hazard Ratios between the two groups³. Adjuvant

Chemotherapy

Hazard Ratio (pCR and EFS) 95% PI

Yes¹ 0.36 0.19-0.67

No² 0.36 0.27-0.54

1>90% of patients received adjuvant chemotherapy 2No more than 10% of patients received adjuvant chemotherapy

3Paired T-test (difference in log-HR: 0.02, 95% PI: -0.75- 0.73; p = 0.60)

Event Free Survival

Metaanalysis confirmed what we knew before

• Now including more nearly 2-fold more patients (27,895), but with most new data derived from retrospective cohort studies

• Novel analytical method that simulates individual patient data analysis without requiring the actual data New information

• No benefit from additional adjuvant chemotherapy if pCR to NACT

• Model to project trial level EFS improvement associated with improved pCR rates Remaining challenges

• Large improvements in pCR (> 20%) required to achieve detectable and clinically meaningful improvements in EFS at the trial level

Spring et al. SABCS 2018; Clin Cancer Res 2020 (PMID: 32046998 )

(24)

Measurement of Residual Breast Cancer Burden to Predict Survival After Neoadjuvant Chemotherapy

http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3

ER-Neg ER-Pos All Patients

Symmans et al. J Clin Oncol 2007; 25:4414-4422 (PMID: 17785706)

(25)

Soru 2. Bu Hastada Hangisi Sistemik Tedavi Kararını Etkilemez ?

1. Evre

2. ER/PR/HER2 3. BRCA

4. PDL1

(26)

Soru 3. Neoadjuvan Tedavi ile İlgili Olarak Yanlış Olan Hangisidir ?

1. T2< tümörlerde pCR ile genel sağkalım ilişkili bulunmuştur

2. Antrasiklin-Taksana Platin eklenmesi olaysız sağkalım (EFS) katkısı sağlamaktadır

3. Antrasiklin-Taksan-Platine karşılık bu kombinasyona PARP inhibitörü eklenmesi olaysız sağkalım (EFS) katkısı sağlamamıştır

4. Standart tedaviye Pembrolizumab eklenmesi PDL1’den bağımsız patolojik tam yanıtları arttırmaktadır

5. Standart tedaviye Pembrolizumab eklenmesi PDL1’den bağımsız genel sağkalım katkısı sağlamıştır

(27)

pCR Sonrası Sağkalım Katkısı

>2cm Tümörlerde Net

Cortozar Lancet 2014

(28)

M14-011 BrighTNess Study Schema

Geyer C, et al. ASCO 2017

Stratification Factors:

• Germline BRCA1/2 status

• Node status

• Schedule of AC

M14-011 BrighTNess pCR Rates

Loibl S, et al. Lancet Oncology. 2018; 19:497-509 53%

31%

Followed by AC

BrighTNess Study: Addition of Neoadjuvant Carboplatin Improves pCR and EFS

Loibl et al. Lancet Oncol 2010 (PMID:

29501363) and ESMO 2021

(29)

Loibl S, Lancet Oncol 2018, JAMA Oncol 2021 ESMO 2021

(30)

Loibl S, Lancet Oncol 2018, JAMA Oncol 2021 ESMO 2021

BL vs Non-BL pCR benzer BL ve IM + pCR+

(31)

Schmid P, et al. N Engl J Med 2020;382:810-21 (PMID: 32101663); IA4 presented at ESMO Virtual Plenary Session 7/16/21

(32)

KEYNOTE 522 Hasta

Özellikleri

Schmid NEJM 2020

(33)

Pathological Complete Response

0 10 40 30 20 50 60 90 80 70 100

pCR,%(95%CI) 64.8%

51.2%

Δ 13.6 (5.4–21.8) P=0.00055

a

0 10 40 30 20 50 60 90 80 70 100

pCR,%(95%CI) 59.9%

45.3%

Δ 14.5 (6.2–22.7)^a

68.6%

53.7%

Primary Endpoint Secondary Endpoints: Other pCR Definitions

ypT0/Tis ypN0 ypT0 ypN0 ypT0/Tis

aEstimated treatment difference based on Miettinen & Nurminen method stratified by randomization stratification factors.

Data cutoff date: September 24, 2018.

Δ 14.8 (6.8–23.0)^a

260/401 103/201

Pembro + Chemo

Placebo + Chemo 240/401 91/201 275/401 108/201

Schmid NEJM 2020

(34)

pCR

0 10 40 30 20 50 60 90 80 70 100

pCR,%(95%CI) 64.8%

51.2%

0 10 40 30 20 50 60 90 80 70

PD-L1–Positive PD-L1–Negative

pCR,%(95%CI)

Primary Endpoint: ypT0/Tis ypN0 By PD-L1 Status^b: ypT0/Tis ypN0

Δ 13.6 (5.4–21.8) P=0.00055

a

100

68.9%

54.9%

Δ 14.2 (5.3–23.1)^a

45.3%

30.3%

Δ 18.3 (–3.3–36.8)^a

aEstimated treatment difference based on Miettinen & Nurminen method stratified by randomization stratification factors. ^bPD-L1 assessed at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor cells x 100); PD-L1–positive = CPS ≥1. Data cutoff date: September 24, 2018.

260/401 103/201 230/334 90/164 29/64 10/33

Pembro + Chemo Placebo + Chemo

Schmid NEJM 2020

(35)

35

Keynote 522 – Results at IA1 and IA2: Improved pCR and EFS

(36)

Keynote 522 – Results at IA4: Neoadjuvant/Adjuvant Pembrolizumab Improves EFS

(37)

Keynote 522 – Results at IA4: Neoadjuvant/Adjuvant Pembrolizumab Improves EFS If Residual Disease after Neoadjuvant Chemotherapy

(38)

38

Keynote 522 – Results: PD-L1 (CPS Score) Prognostic but Not Predictive of Benefit from Pembrolizumab for both pCR or EFS

(39)

3yr 77.2%

3yr 85.6%

Stratified HR* Durvalumab to Placebo = 0.48 (95%CI 0.24, 0.97), p=0.0398

Time (months)

Invasive Disease-Free Survival Rate (%)

Patients at risk:

GeparNUEVO: Phase II Durvalumab Neoadjuvant Trial

12 weeks

Surgery

Nab-Pac +Durvalumab

N=174 TNBC

Stratum:

TILs

(low/med/high)

R

2 weeks

ECx4 +Placebo

8 weeks Window of opportunity

until amendment

Durvalumab (0.75g) 1.5g d1q28

nab-paclitaxel 125mg/m² weekly

Clinical response

Durvalumab

Placebo

Core biopsy Nab-Pac

+Placebo

ECx4 +Durvalumab

Samples Samples Samples Samples

Epirubicin 90mg/m²;

Cyclophosphamide 600mg/m² d1q14

Primary endpoint:

pCR (ypT0, ypN0)

Main secondary endpoints:

iDFS, DDFS, OS

Loibl S, et al. Ann Oncol 2019; Loibl et al, ASCO 2021 Primary endpoint: pCR – ypT0, ypN0

53.4%

44.2%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Durvalumab Placebo

Adjusted** OR 1.53 [95%CI 0.82-2.84]

p=0.182 P=0.287*

~35% stage 1

iDFS between arms

Median FU 43.7 months

* Stratified by sTILs

(40)

Randomized trials neoadjuvant atezolizumab in TNBC

Mittendorf et al. Lancet 2020 396(10257):1090-1100 (PMID: 32966830)

NeoTRIPaPDL1:

Atezolizumab (PD-L1 inh) x 8 (n=280)

Randomization

Atezo

Carboplatin + nab-paclitaxel

Surgery

Anthracycline + cyclophosphamide

Placebo Carboplatin + nab-paclitaxel

(41)

Olgu; Sistemik Tedavi

• 4 kür Karboplatin-Paklitaksel+ Pembro/ Plasebo

• Klinik ve Radyolojik Tam Yanıt +

• 4 AC+ Pembro/ Plasebo

• Periodentit+, İYE+, blefarit+, Artrit?

(42)

NEOADJUVAN TEDAVİ SONRASI

(43)

Soru 4. Neoadjuvan Tedavi Sonrası Değerlendirmede Hangisi Yanlıştır ?

1. İlk değerlendirme hangi yöntem ile (US vs MR) yapılmışsa yanıt aynı yöntem ile değerlendirilmelidir

2. Cerrahi kararı (MKC vs Mastektomi) yanıt sonrası tümöre göre karar verilmelidir

3. Cerrahi son kemoterapiden 2-8 hafta içinde yapılmalıdır 4. Cerrahi sınır yönetimi primer tümöre göre karar verilmelidir 5. NAT sonrası sentinel lenf nodu örneklemesi güvenilirdir

(44)

Cerrahi

Sol MRM-SLNÖ-ALND, sağ simple mastektomi

Pat: patolojik tam yanıt +

(45)

Olgu; Sistemik Tedavi

• 4 kür Karboplatin-Paklitaksel+ Pembro/ Plasebo

• Klinik ve Radyolojik Tam Yanıt+

• 4 AC+ Pembro/ Plasebo

• Periodentit+, İYE+, blefarit+, Artrit?

• Cerrahi (26/12/2018)

• Adj RT (05/02/2019 - 18/3/2019)

• Adj Pembro/ Plasebo (01.04.2019 - 13/09/2019)

(46)

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy

Masuda et al. N Engl J Med. 2017 Jun 1;376(22):2147-2159 (PMID: 28564564)

(47)

(48)

(49)

EA1131

Mayer et al. J Clin Oncol 2021;39(23):2539-2551 (PMID: 34092112)

(50)

EA1131 – Results: Adjuvant platinum not better than capecitabine in residual TNBC after prior taxane-containing neoadjuvant chemotherapy

3-year iDFS by Treatment in <br />Patients with Basal Subtype TNBC

Content of this presentation is the property of the author, licensed by ASCO. Permission required for reuse.

5th Interim Analysis – January 2021

3-year iDFS by Intrinsic Subtype and Treatment

Selected Adverse Events and Drug Exposure

Mayer et al. J Clin Oncol 2021;39(23):2539-2551 (PMID: 34092112)

(51)

The Institute of Cancer Research and Kings College London

Andrew Tutt MB ChB PhD FMedSci

131

Time since randomization (months)

921 820 737 607 477 361 276 183

915 807 732 585 452 353 256 173

Olaparib Placebo

0 6 12 18 24 30 36 42

0 20 40 60 80 100

Invasive disease-free survival (%)

Olaparib (106 events) Placebo (178 events)

Stratified hazard ratio 0.58 (99.5% CI, 0.41‒0.82); P<0.0001 88.4

93.3

81.5

89.2 85.9

77.1

No. at risk

Difference: 3-year IDFS rate 8.8% (95% CI, 4.5‒13.0%)

OlympiA: Invasive disease-free survival (ITT)

Tutt et al. NEJM 2021 (PMID: 34081848)

(52)

The Institute of Cancer Research and Kings College London Andrew Tutt MB ChB PhD FMedSci

OlympiA: Invasive disease-free survival (mature cohort)

133

Stratified hazard ratio 0.61 (99.5% CI, 0.39‒0.95)*

88.0 93.7

81.9

89.6 86.1

77.5

449 399 378 365 343 324 276 183

451 396 378 361 340 321 256 173

Olaparib Placebo No. at risk

Difference: 3-year IDFS rate 8.6% (95% CI, 3.3‒13.9%)^†

0 6 12 18 24 30 36 42

0 20 40 60 80 100

Invasive disease-free survival (%)

First 900 patients entered with median follow up of 3.5 years

*Stratified Cox proportional hazards model, ^†Kaplan–Meier estimates

(53)

134

OlympiA: Distant disease-free survival

OS P<0.01

IDFS P<0.005

Recycling of alpha for conservation

future analyses DDFS

P<0.005 DDFS and

OS only tested if IDFS

significant

921 823 744 612 479 364 279 187

915 817 742 594 461 359 263 179

Stratified hazard ratio 0.57 (99.5% CI, 0.39‒0.83); P<0.0001 90.2

94.3

83.9

90.0 87.5

80.4

Difference: 3-year DDFS rate 7.1% (95% CI, 3.0‒11.1%)

Olaparib Placebo No. at risk

Distant disease-free survival (%)

0 6 12 18 24 30 36 42

0 20 40 60 80 100

(54)

The Institute of Cancer Research and Kings College London Andrew Tutt MB ChB PhD FMedSci

135

OlympiA: Overall survival

921 856 801 659 531 400 310 205

915 865 801 659 516 397 292 199

Olaparib Placebo

0 6 12 18 24 30 36 42

Time since randomization (months) 0

20 40 60 80 100

Overall survival (%)

Olaparib (59 deaths, 55 due to breast cancer)

Stratified hazard ratio 0.68 (99% CI, 0.44‒1.05); P=0.024

not significant based on level of P<0.01 in IA alpha spending plan 96.9

98.1

92.3

94.8 92.0

88.3

Placebo (86 deaths, 82 due to breast cancer)

No. at risk

Difference: 3-year overall survival rate 3.7% (95% CI, 0.3‒7.1%)

(55)

136

OlympiA: Subgroup analysis invasive disease-free survival

No statistical evidence of heterogeneity between any subgroup and the ITT IDFS treatment effect

HR status Prior platinum Prior chemo

0.555 (0.411–0.745) 117 / 460

70 / 460 Neoadjuvant

0.144 0.773 (0.490–1.209)

43 / 239 34 / 247

Yes

0.520 (0.389–0.689) 135 / 676

72 / 674 No

0.509 0.701 (0.381–1.268)

25 / 157 19 / 168

HR+/HER2-

0.563 (0.431–0.730) 153 / 758

87 / 751 TNBC

0.581 (0.455–0.737) NA 178 / 915

106 / 921 All patients

Subgroup Olaparib Placebo Stratified hazard ratio for invasive-disease-free survival P value for heterogeneity No. of patients with an invasive-disease

event/total no.

BRCA 0.998

0.524 (0.389–0.699) 126 / 558

70 / 558 BRCA1

0.515 (0.300–0.862) 38 / 209

22 / 230 BRCA2

NC 0 / 3

0 / 1 BRCA1/2 both

0.763 0.601 (0.394–0.901)

61 / 455 36 / 461

Adjuvant

Favors olaparib Favors placebo

0.25 0.50 0.75 1.00 1.25