Unmet Challenges in Breast Cancer(and opportunities for international collaboration)

Eric P. Winer, MDDana-Farber Cancer Institute

Harvard Medical SchoolBoston, USA

Breast Cancer Incidence and Deaths in the U.S.

Greater than 30%decline in death rate

Worldwide Breast Cancer Incidence and Deaths

•Over 1.7 million diagnoses each year

•Over 500,000 deaths each year

Unmet Challenges• Drug resistance

▪ Triple negative disease

▪ Luminal B disease

▪ Brain metastases

• Late recurrence▪ ER+ disease (probably both HER- and HER2+)

• Disparities▪ Young women

▪ Older women

▪ Racial

▪ Socioeconomic

▪ Geographic

Two Additional Challenges

•Over diagnosis

•Overtreatment

Of the two, overtreatment an easier problem to solve but still very challenging

The Problem of Late Recurrence in ER+ Disease

• Longstanding problem, but increasingly recognized

• Over two thirds of all breast cancer deaths due to ER+ disease, and more than half result from recurrences that arise more than 5 years after diagnosis

• HOWEVER, annual event rate is relatively low, especially for lower risk patients

• Urgent need▪ Better predictors of late recurrence

▪ More effective agents to prevent recurrence

Effects of Hormonal Therapy for Early Breast Cancer on Recurrence: EBCTCG Analysis

Early Breast Cancer Trialists’ Collaborative Group. The Lancet 2005:365:1687-1717.

Annual and Cumulative Risk of Late Recurrence by Subset in Women Disease Free at 5 Years

Hayes et alNEJM 2017

Disease-free Survival Overall Survival

Aromatase inhibitors versus tamoxifen in early breast

cancer: patient-level meta-analysis of the randomised trials

EBCTCG. Lancet 2015;386:1341-52.

TAM 5 vs AI 5 TAM 2-3 AI 2-3 vs AI 5

BIG 1-98: Long-term outcomes

Thurlimann B, et al. SABCS 2016

Major trials of extended adjuvant endocrine therapy

Treatment 0 2 3 5 10 15

MA17

NSABP B-33

ABCSG 6a

ATLAS

ATTOM

MA17R

NSABP B-42

IDEAL

DATA

TAMAI

Years since diagnosis

MA 17: Letrozole or Placebo after 5 years of Tamoxifen

Goss PE et al. N Engl J Med 2003;349:1793-1802. Ingle J N et al. Ann Oncol 2008;19:877-882

DFS and OS Contralateral BC

Goss PE et al. N Engl J Med 2016;375:209-19

DFS and OS Contralateral BC

MA17R: Extended AI Therapy

None of the more recent trials have increased the enthusiasm for extendedAI therapy after previous AI –if anything, less than 5 years may be as good as 5 years

DFS 5 years2.5y: 88.4%

5y: 87.9%

HR: 0.96 (0.76-1.20)P-value: 0.70

IDEAL Study

C.J.H. van de Velde et al. SABCS 2016

Frequency of ctDNA ESR1 mutations in ER+ MBC

Study ESR1 mut

BOLERO2* (N=541) 28.8%

SOFeA** (N=161) 39.1%

PALOMA 3** (N=360) 25.3%

FERGI§ (N=70) 37%

*D538G and Y537G**E380Q, L536R, Y537C, D538G, S463P, Y537N, and Y537S§E380Q, S463P, P535H, L536Q, L536R, L536H, L536P, Y537C, Y537N, Y537S, D538G

Chandarlapaty S. et al. JAMA Oncol. 2016;2(10):1310-1315Fribbens C. et al. J Clin Oncol. 2016 Sep 1;34(25):2961-8Gendreau S. et al. SABCS 2015

16. Courtesy of Mafalda Oliveira

ESR Mutations: Implications

• Emergence of ESR seems to arise under selective pressure in setting of AI therapy

• These mutations convey resistance to AI therapy and limit the effectiveness of such treatment

• ESR mutations may account for the limited benefit of extended AI therapy

The Current Reality

• Late recurrence is clearly a major source of morbidity and mortality after 5 years of tamoxifen

• The AIs reduce risk of early and late recurrence to a small degree

• Extended use of AI therapy is marginally effective

• Trials of early use of CDK 4/6 inhibitors may lead to lower early and possibly late recurrences, though the former seems more plausible

• We need new approaches

Recurrence Score and Prediction of Late Distant Recurrence After 5 years of Tamoxifen: NSABP B-14

RS Group N (%) of pts

% distant recurrence5 to 10 years

% distant recurrence5 to 15 years

Low 289 (58%)

4.7% 6.8%

Intermediate 111 (22%)

4.1% 11.2%

High 97 (20%) 12.6% 16.4%

Wolmark N, et al.J Clin Oncol 32:5s, 2014 (suppl; abstr 11024)

Paik et al. NEJM 2004;351:2817

Distant recurrence over 10 years for node-negative

patients by PAM50 ROR score in ATAC trial

Ivana Sestak et al. JCO 2015;33:916-922

Garcia-Murillas … Nicholas Turner et al Sci Transl Med, 2015

Mutation Tracking in Circulating Tumor DNA Predicts Relapse in Early Breast Cancer

21

Isaac Garcia-Murillas et al., Sci Transl Med 2015;7:302ra133

Published by AAAS

Single Mutation Tracking of MRD: Preliminary Data but Highly Specific To Date

22

Garcia-Murillas … Nicholas Turner et al Sci Transl Med, 2015

Tracking breast cancer: a future vision

23

Potential Clinical Trial

Patients with Stage II/IIIER+ Disease 10 Years

Post-Diagnosis Off Therapy

Every 6 monthMeasurement of

ctDNA

Standard Care

No ct DNA ct DNA Detected BEGIN NEW THERAPYContinue to Follow

Arm A

Arm B

Endpoint: DFS and OS Arm A vs B

Will Take Several Thousand Patients and Broad Collaboration

The Problem of Overtreatment

• Occurs for both local and systemic therapy

• A consequence of:

▪ Overdiagnosis due to screening (if patient did not need to be diagnosed, then treatment is not needed)

▪ Increasingly effective therapy

• Most trials have focused on improving overall outcomes by adding therapies

• Many clinicians fear “rocking the boat” and understandably do not want to put patient at higher risk of recurrence

• Toxicity of therapy is often underappreciated

Where Can We Begin?

• In settings where outcomes are excellent

• Even if treatment is of limited value, much harder to back off when outcomes are relatively poor

• Most appropriate settings:

▪ Earlier stage disease

▪ Luminal A disease

▪ HER2+ disease treated with targeted theapy

▪ In settings where toxicity may be greater (e.g. the elderly)

Sparano, J. A. et al. J Clin Oncol; 26:721-728 2008

TAILORx

Prospective Validation of 21-Gene RS in Node-Negative Patients: TAILORx

Sparano JA et al. NEJM 2015

Secondary GroupRS <11

Assigned to Hormonal Therapy Only

Distant Relapse Free Survival

99.3%

Invasive Disease Free Survival

93.8%

Overall Survival 98.0%

5 Year Results

German Study Group PlanB Trial:

Outcomes for N0 or N1 (1 to 3 positive nodes) tumors

Oleg Gluz et al. JCO 2016;34: epub ahead of print

3-year DFS inRS < 12 with ET, only

N0 98.6%N1 97.9%

Unlikely that chemotherapy will meaningfully improve prognosis.At the extremes, a prognostic marker becomes predictive.

Cardoso F et al.N Engl J Med 2016;375:717-729.

MINDACT: Survival without Distant Metastasis, Disease-free Survival, and Overall Survival in the Two Discordant-Risk Groups, According to Randomized Treatment

TAILORx Results

Node NegativeER+

Oncotype 11-25

Chemotherapy plusHormonal Therapy

Hormonal TherapyAlone

?????Await Results

At ASCO

Questions to be Addressed in Luminal A Disease

• Can we give shorter duration endocrine therapy to the lowest risk group?

• What about clinical high risk disease (4+ nodes)?

▪ Is chemotherapy needed?

▪ What other treatments can lower risk?

✓Seems unlikely that CDK 4/6 inhibitors will provide the whole answer

• How do we define the cutoffs for genomic assays when we are looking at prediction and not just pronostication

APT: Study Design

HER2+

ER+ or ER-

Node Negative

< 3 cm

Enroll

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12

TT T T T T T T T T T T T

FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg)*

N=410

Tolaney et al, NEJM 2015

Disease-Free Survival Events

Tolaney et al, ASCO 2017

DFS Event N (%) Time to event

[months; mean(range)]

Any recurrence or death 23 (5.7)

Local/Regional Recurrence*

Ipsilateral axilla (HER2+)

Ipsilateral breast (HER2+)

5 (1.2)

3

2

29 (12-54)

51 (37-65)

New Contralateral Primary Breast Cancer

HER2+

HER2-

Unknown

6 (1.5)

1

3

2

56

36 (12-59)

87 (84-90)

Distant Recurrence 4 (1.0) 49 (27-63)

Death

Non-breast cancer related 8 (2.0) 58 (13-71)

APT: Updated Recurrence Free Interval

Point Est. 95% Conf.

Interval

No. of

events

3-yr RFI 99.2% 98.4% to >99.9% 3

5-yr RFI 98.1% 96.8% to 99.5% 7

7-yr RFI 97.5% 95.9% to 99.1% 9

RFI Events

•Invasive

Local/Regional

Recurrence

•Distant Recurrence

•Death from Breast

Cancer

Tolaney et al, ASCO 2017

Use of Path CR as Powerful Biomarker to De-escalate Therapy

• Demonstrated in multiple individual trials

• Demonstrated in Cotezar overview

• Demonstrated by GBG in multiple studies

• And most recently….

pCR is a highly significant predictor of EFS and DRFS

38

San Antonio Breast Cancer Symposium, Dec 5-9, 2017

EFS DRFSOVERALL

pCR is predictive of EFS and DRFS in HR+/HER2–

39

I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017

EFS DRFS

pCR is predictive of EFS and DRFS in HR–/HER2+

40

I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017

HR-HER2+EFS DRFS

A Design to Decrease Treatment, Assess Resistance, and Test New Therapies

Stage II/IIIHER2+

Highly Active Therapy (THP)

Comprehensive Tissue/BloodCollection and Analysis

No pCR

pCR

Standard Treatment

ExperimentalTreatment

Sample size will depend on confidence intervals for phase II study of CR patients

and phase III of high risk patients (almost certainly < 2000)

Target RFS Approximately93-95% at 3-5 years

A Trans-Atlantic Collaboration is Planned

Problems at the Extremes of Ageand Among Those with Health Care Disparities

Survival of Young Women With Breast Cancer is Inferior to Older Women

Age at diagnosis 5-year relative

survival

<40 84%

40 and older 90%

National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009/, posted to the

SEER web site, 2012

Disease-free Survival by Age

Anders et al. J Clin Oncol 2008

Young Age is Associated with Increased pCR

Loibl et al., BCRT, 2015

N=8949 total; N=1453 < 40

Age was neither a prognostic nor predictive for early recurrence in the HERA Trial: STEPP Analyses According to Age

Partridge et al., J Clin Oncol, 2013

Young Women Are More Likely to Die from Luminal A Tumors in NCCN

All Tumors

N=17,575

Luminal A

N=7738Luminal B

N=5149

Triple Negative

N=2886

Haz

ard

Rat

io

Partridge et al., SABCS 2011, JCO 2016

Younger and Much Older Women are

More Likely to be Non-Adherent

Hershman et al, JCO 2010

Worse Outcomes for Older WomenStage I (n = 226,347)

Time since diagnosis (years)C

um

ula

tive incid

ence

0 5 10 15

0.0

00.2

50.5

00.7

51.0

0

<=35

36 ~ 44

45 ~ 54

55 ~ 64

65 ~ 74

75 ~ 84

85+

Stage II (n = 169,973)

Time since diagnosis (years)

Cum

ula

tive incid

ence

0 5 10 15

0.0

00.2

50.5

00.7

51.0

0

Stage III (n = 65,081)

Time since diagnosis (years)

Cum

ula

tive incid

ence

0 5 10 15

0.0

00.2

50.5

00.7

51.0

0

Stage IV (n = 24,717)

Time since diagnosis (years)C

um

ula

tive incid

ence

0 5 10 15

0.0

00.2

50.5

00.7

51.0

0

Kaplan-Meier estimates of the cumulative incidence of breast cancer-specific deaths by stage at diagnosis. Within each

stage, cumulative incidence is plotted for all age groups from the youngest (blue) to oldest (orange) cohorts

Freedman et al Cancer 2018; in press

We have come together internationally to study the problem of breast cancer in young

women, but little has been done to tackle the higher mortality rate seen in older

women

Both areas require continued efforts

International Collaborations

• Always more complicated

• But results more generalizable

• Trials move more rapidly

• Duplication avoided

• Needed in settings where patient populations are limited and/or sample size needs to be large

• The investment is well worth the gains

Thank you