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Unmet Challenges in Breast Cancer(and opportunities for international collaboration)
Eric P. Winer, MDDana-Farber Cancer Institute
Harvard Medical SchoolBoston, USA
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Breast Cancer Incidence and Deaths in the U.S.
Greater than 30%decline in death rate
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Worldwide Breast Cancer Incidence and Deaths
•Over 1.7 million diagnoses each year
•Over 500,000 deaths each year
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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
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Two Additional Challenges
•Over diagnosis
•Overtreatment
Of the two, overtreatment an easier problem to solve but still very challenging
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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
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Effects of Hormonal Therapy for Early Breast Cancer on Recurrence: EBCTCG Analysis
Early Breast Cancer Trialists’ Collaborative Group. The Lancet 2005:365:1687-1717.
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Annual and Cumulative Risk of Late Recurrence by Subset in Women Disease Free at 5 Years
Hayes et alNEJM 2017
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Disease-free Survival Overall Survival
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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
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BIG 1-98: Long-term outcomes
Thurlimann B, et al. SABCS 2016
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Garcia-Murillas … Nicholas Turner et al Sci Transl Med, 2015
Mutation Tracking in Circulating Tumor DNA Predicts Relapse in Early Breast Cancer
21
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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
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Tracking breast cancer: a future vision
23
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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
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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
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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)
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Sparano, J. A. et al. J Clin Oncol; 26:721-728 2008
TAILORx
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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
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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%
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Unlikely that chemotherapy will meaningfully improve prognosis.At the extremes, a prognostic marker becomes predictive.
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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
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TAILORx Results
Node NegativeER+
Oncotype 11-25
Chemotherapy plusHormonal Therapy
Hormonal TherapyAlone
?????Await Results
At ASCO
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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
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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
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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)
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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
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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….
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pCR is a highly significant predictor of EFS and DRFS
38
San Antonio Breast Cancer Symposium, Dec 5-9, 2017
EFS DRFSOVERALL
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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
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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
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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
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Problems at the Extremes of Ageand Among Those with Health Care Disparities
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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
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Disease-free Survival by Age
Anders et al. J Clin Oncol 2008
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Young Age is Associated with Increased pCR
Loibl et al., BCRT, 2015
N=8949 total; N=1453 < 40
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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
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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
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Younger and Much Older Women are
More Likely to be Non-Adherent
Hershman et al, JCO 2010
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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
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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
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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
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Thank you