Neoadjuvant Therapy for - PowerPoint Presentation

Slide1
Slide2

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

sisakoff@partners.orgSlide3

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 seenUltrasound-guided core needle biopsy with clip placement was performed and revealed a triple negative, poorly differentiated (grade 3) infiltrating ductal carcinoma with LVI presentBilateral breast MRI confirmed known mass, no other suspicious findings. All visible nodes appeared morphologically normal.Genetic testing sent, BRCA1/2 negativeWhat would you recommend for treatment?

TNBC CaseSlide4

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 2/3Improve breast conservation rates and reduce extent of breast surgeryReduce extent of axillary surgeryMay allow risk stratification to guide adjuvant therapy selectionNovel therapy developmentProvide prognostic information as surrogate for disease free survivalFuture role?:Allow risk stratification and de-escalation of therapySlide5

Association of pCR with Event Free Survival in Triple Negative Breast Cancer

Cortazar

SABCS 2012FDA Meta-analysisSlide6

Ongoing Controversy: Platinum AgentsWhat is the role of platinum in neoadjuvant therapy for TNBC in 2017?Slide7

Cisplatin and Breast CancerSledge 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 patientsRenewed interest in patients with triple negative breast cancerAssociation of TNBC and BRCA1Slide8

Platinum for Neoadjuvant Therapy in Sporadic TNBC and BRCA1 Mutation Carriers

Sporadic TNBC

> 2cm, Stage II/ IIIResearch Core BiopsyN=28

Cisplatin 75mg/m

2

q3wks x 4 cycles

Assess Response



Standard Adjuvant Therapy per MD

pCR

22%

Garber et al, SABCS 2006; Silver et al, JCO 2010Slide9

ALLIANCE/CALGB 40603 Study evaluating addition of Carboplatin and Bevacizumab in Neoadjuvant Tx for Triple Neg Breast Cancer

N=443

ER/PR/HER2-Stage II-IIIBSikov J Clin Oncol 2015. 33:13-21Slide10

Sikov J Clin Oncol

2015. 33:13-21

Carboplatin improves pCRALLIANCE/CALGB 40603 Study evaluating addition of Carboplatin and Bevacizumab in Neoadjuvant Tx for Triple Neg Breast CancerSlide11

CALGB 40603 – Event –free survival for carboplatinSlide12

GeparSixto Trial:Neoadjuvant carboplatin for Triple Negative Breast Cancer315 pts

(~53% TNBC)

40% node posSlide13

GeparSixto: Carboplatin improves pCR for Triple Negative Breast CancerSlide14

pCR Rates by germline BRCA status and Carboplatin in TNBCgBRCA are highly sensitive to chemotherapyPlatinum does not add benefit to

gBRCA

pCR

55.0%

36.4%

OR 2.14

(1.28-3.58

)

P=.004

OR 0.94 (0.29-3.05

)

P= 0.92

66.7%

65.4%

Von

Minckwitz

, Lancet Oncology, 2014;

Hahnen

, JAMA

Onc

, 2017Slide15

Disease-free Survival: Effect of Carboplatin in TNBC

von Minckwitz et al. SABCS 2015

Median DFS Follow-up = 35 months Slide16

TILs in TNBC associate with improved pCR with platinum in GeparSixto

Denkert

C, JCO 2015Slide17

Role of Platinum in Neoadjuvant TNBCSlide18

TBCRC 030: Neoadjuvant Cisplatin vs Paclitaxel in TNBCPrimary 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 DeficiencyTNBC >1.5 cmCisplatin75 mg/m2 q 3 wk x 4Paclitaxel

80 mg/m2

q

wk

x 12

Tissue Collection

Tissue Collection

Surgery

Complete

Adjuvant

Chemotherapy

Stratification

LN + vs –

T1/2 vs T3/4

PI: Erica Mayer, DFCISlide19

Randomized Phase II trial:

Neoadjuvant Cisplatin vs AC

in Women with Germline BRCA MutationsN. Tung, PI

Is cisplatin better than AC for preoperative therapy for BRCA carriers?Slide20

Schema: INFORM trial

Primary aims:

pCR and Residual Cancer Burden (designed to show 20% improvement with cisplatin over AC)Secondary aim: biomarkers of responseEligibility: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=85

N=170 (90 enrolled)

Multicenter studySlide21

Does platinum improve long term outcome:Adjuvant Platinum TherapySlide22

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 resultsAddition 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 +/- carboplatinStandard combination chemotherapy remains the standard of careIn selected cases, adding platinum is reasonable for improved local controlSlide23

Can we use pCR/RCB in TNBC to reduce treatment?

Carboplatin

/taxane

Surgery

x 4-6

cycles

No

pCR

/

RCB 2/3

Yes

pCR

/

RCB 0/1

Adriamycin

/

cytoxan

x 4

No further therapy

Adriamycin

/

cytoxan

x 4

Hypothetical design:

Non-inferiority trial

HR boundary 1.15

HYPOTHETICAL TRIALSlide24

Prospective Registry Study of AC-T and

Taxotere

/Carbo x 6 and impact of pCRCarboplatin/Docetaxel pathological response by gBRCA statusComparison 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 2016Slide25

Masuda et al. NEJM 2017; Lee,

Toi

et al. SABCS 2015

Management of Residual Disease After

Neoadjuvant

TherapySlide26

CREATE-X: Adjuvant Capecitabine for non-pCR

Masuda et al. NEJM 2017; Lee,

Toi

et al. SABCS

2015Slide27

Management of Residual Disease After Neoadjuvant TherapySlide28

Novel therapies for neoadjuvant TNBCSlide29

I-SPY 2 TRIAL Schema: HER2- Signatures

Presented By Rita Nanda at 2017 ASCO Annual Meeting

Immunotherapy in Pre-operative breast cancerSlide30

Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN

Presented By Rita Nanda at 2017 ASCO Annual Meeting

Immunotherapy in Pre-operative breast cancerSlide31

Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN

Presented By Rita Nanda at 2017 ASCO Annual Meeting

Immunotherapy in Pre-operative breast cancer

Pembrolizumab

graduated to phase 3 – the Keynote 522 studySlide32

The future: Targeting the Heterogeneity of TNBCSlide33

Heterogeneity in response to neoadjuvant chemotherapyMasuda et al Clin Cancer Res; 19(19) October 1,

2013Slide34

Potentially Actionable Mutations in post-Neoadjuvant Chemotherapy with residual disease

Balko

, Cancer Discovery 2014;4:232-245Slide35

Neoadjuvant Therapy with Ipatasertib

(AKT inhibitor) with paclitaxel

1L

mTNBC

STRATIFY:Adjuvant

or

neoadj

(y/n), PTEN

status (null

vs

h-score 1 to 150

vs

>150)

R

Schema: LOTUS study

Taxol weekly +

Ipatasertib

400mg QD (3wk on/1wk off)

Taxol

weekly + Placebo

n = 120

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 2017Slide36

Neoadjuvant Therapy with Ipatasertib (AKT inhibitor) with paclitaxel

Neoadjuvant

T>1.5 cm

STRATIFY:PTEN

status (null

vs

h-score 1 to 150

vs

>150), node, size

R

Schema:

FAIRLANE Study

Taxol weekly +

Ipatasertib

400mg QD (3wk on/1wk off) x 12 wks

Taxol

weekly + Placebo x 12 wks

n = 150

Primary endpoint:

pCR

in ITT and PTEN low

Secondary endpoint:

pCR

in PTEN low/PIK3CA/AKT altered

Surgery

FAIRLANE Completed

Accrual Summer 2017

Results to be presented ASCO

2018

Phase 3 study underway in 1

st

metastatic TNBC (and ER+)Slide37

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

.

Summary and Take-Home PointsSlide38

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 seenUltrasound-guided core needle biopsy with clip placement was performed and revealed a triple negative, poorly differentiated (grade 3) infiltrating ductal carcinoma with LVI presentBilateral breast MRI confirmed known mass, no other suspicious findings. All visible nodes appeared morphologically normal.Genetic testing sent, BRCA1/2 negativeWhat 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

TNBC CaseSlide39

Thank yousisakoff@mgh.harvard.edu

Acknowledgments

Eric WinerNadine TungErica MayerLaura Spring