when is chemotherapy needed for luminal b advanced breast

When is Chemotherapy needed for Luminal B

Advanced Breast Cancer ?

Dr. Paul N Mainwaring

Brisbane, Australia

Disclosures; last 10 years

• Advisory Boards, Company Shares/Ownership; Invited Lectures; Research Funding

• Astellas, AstraZeneca, BMS, Eisai, Genentech, GSK, Ipsen, Janssen/JnJ, Lilly, Medivation, Merck, Novartis, Pfizer, Roche, XING Technologies

Outline

• Definition of Luminal ABC• DNA, epigenetic, RNA, Protein

• Endocrine therapy• SERM, SERD, CDK4/6i, mTORi reviewed by Dr Yap

• Chemotherapy• When do I introduce ?

• Which drugs ?

• Which schedule and why ?

• pK; Dose modification

• pK: Dose interruption

• pD; surrogate measures of efficacy (NLR, neuts, rash etc)

• Can biology help guide treatment ?

• Immunotherapy• Immune checkpoint-therapy

• Other approaches

Endocrine therapy

How do we define Luminal Breast Cancer?

Intrinsic Subtypes by

Gene Expression Profiling

HER2 +

ER and/or PR +

Low/high grade

Low/high

proliferative index

HER2 -

ER/PR+ (low expression) OR

ER+/PR- OR ER-/PR+

High grade/ High proliferative index (Ki67)

Derived from cDNA microarray now RNA-Seq (PAM50)

In reality, most pathology reports use protein immunohistochemistry

ER+/PR+ (high expression)

Low grade

Low proliferative index (Ki67)

HER2 -

LUMINAL A LUMINAL B (Heterogeneous group)

Chemotherapy

Chemo-

immunotherapyPerou Nature 2000

Sørlie PNAS 2001

CornejoAPLM 2014

Vasconcelos Breast 2016

Questions

1. What are the goals of treatment after endocrine therapy ?

2. Is there a role for chemotherapy in general in this setting ?

3. Is there a subset of patients who may benefit more ?

1. De-novo endocrine resistant disease

2. Acquired endocrine resistant disease

3. Visceral crisis

• Can we go back to endocrine therapy after chemotherapy ?

• “Maintenance therapy”

Treatment Algorithm Luminal ABC

Luminal A

HER2 neg

Luminal B

HER2 neg

Triple positive

No

visce

ral crisis

CDK4/6i

Endocrine Tx

CDK4/6i

Endocrine Tx

PFS1

Everolimus

Exemestane

Everolimus

Exemestane

SERD

Chemo

therapy

No

visce

ral crisis

Chemo

PFS2 PFS3 PFS4

Chemo

PFS5

Overall Survival

T-DM1

Taxane/Pert/Trast

AI/Trastuzumab

Lap/Cape

Chemo/

trast

ABC4

Chemotherapy doesn’t

make the list

Chemotherapy doesn’t

make the list

ASCO

Rugo JCO 2018

Questions






3. Visceral crisis



Cochrane Database Syst Rev 2003

RR Chemotherapy vs Endocrine Therapy ABC

Cochrane Database Syst Rev 2003

OS Chemotherapy vs Endocrine Therapy ABC

Subsequent therapy; reduction in Rx

Study 2nd Line 3rd Line 4th Line 5th Line

Dufresne et al. (2008) 100% 56% 25% 11%

Tacca et al. (2009) 100% 68% 43% 23%

Bernardo et al. (2010) 100% 82% 36% 11%

Planchat et al. (2011) 100% 76% 56% 37%

Current Jackisch (2014) 100% 70% 46% 27%

Jackish SABCS 2016

Clinical Efficacy of Chemotherapeutic Agents in Each Line of Therapy

Basaran Ca Treat Rev 2017

CDK 4/6i + ETx 27.6 mo + OS control arm PALOMA-3 28 = 56 mo

OS

16.9

16.4

17.0

?

OS

16.9

16.4

17.0

?

Eribulin 9.2 4 3

Turner NEJM 2018

Old data but still relevant concepts

Overall SurvivalProgression-Free Survival

Gennari JCO 2011

Pre-HER2/TNBC era

Chemotherapy choices I

• Thoughts not Guideline

• Proliferation is driver• Taxanes: Prior exposure, Disease-free interval

• Anthracyclines: Prior exposure, Disease-free interval

• Capecitabine p.o. outpatient

• Vinorelbine IV p.o.

• DNA repair deficiency; Chromosomal instability• Platinum/doublet first-line ?

• CMF, irinotecan, etoposide

• Wnt pathway/EMT• Eribulin

Wilson BCRT 2017

Rebucci Bio Pharm 2013

PEARL; GEICAM/2013-02

Martin SABCS 2016

Questions






3. Visceral crisis



ABC4

Biological Factors

Low ER

Low PR

High proliferation

Loss PRCardoso Annals 2018

Landscape ER-resistant disease

Razavi Ca Cell 2018

DeNovo resistance

~15-30 %

Acquired resistance

Yap et al. Nature PJ: Breast Cancer 2018

Potential mechanisms resistance CDK4/6i

O’Leary NRCO 2016

ABC4

I would argue continue to biopsy

Tissue or Liquid @ progression

For clinical trial inclusion

I would argue continue to biopsy

Tissue or Liquid @ progression

For clinical trial inclusion

Questions






3. Visceral crisis



Do no harm

Triple Positive

No trials comparing anti-HER2 agent + chemotherapy

Vs. anti-HER2 agent + endocrine therapy

Triple Positive: Anti-HER2 only adds modestly to Endocrine Therapy Improved PFS but not OS

RAnastrozole

HER2+, HR+ MBC (TAnDEM)No prior chemo; prior hormonal therapy allowed

Trastuzumab + Anastrozole

Kaufmann et al. J Clin Oncol, 2009; 27:5529-5537; Johnston et al. J Clin Oncol 2009; 27:5538-5546

RLetrozole

HER2+, HR+ MBC, n=219 No prior treatment for MBC

Lapatinib + Letrozole

4.8 vs 2.4 months

P=0.0016

PFS

OS 28.5 vs 23.9 months, p=0.325

8.2 vs 3.0 months

P=0.019

PFS

OS 33.3 vs 32.3 months, p=0.113

PERTAIN; Triple positive

Rimawi JCO 2018

ALTERNATIVE

PATINA – maintenance therapy

Treatment Algorithm Luminal ABC

Luminal A

HER2 neg

Luminal B

HER2 neg

Triple positive

No

visce

ral crisis

CDK4/6i

Endocrine Tx

CDK4/6i

Endocrine Tx

PFS1

Everolimus

Exemestane

Everolimus

Exemestane

SERD

Chemo

therapy

No

visce

ral crisis

Chemo

PFS2 PFS3 PFS4

Chemo

PFS5

Overall Survival

T-DM1

Taxane/Pert/Trast

AI/Trastuzumab

Lap/Cape

Chemo/

trast

Start

Chemotherapy

Start

Chemotherapy

Re

sist

an

ce

Re

sist

an

ce

Start

Chemotherapy

Start

Chemotherapy

Re

sist

an

ce

Biology

ER, PR, HER2

Proliferation

“Omics

when is chemotherapy needed for luminal b advanced breast

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