Young Women and Breast Cancer:
The Future of Care
Julie R. Gralow, M.D.
Jill Bennett Endowed Professor of Breast Cancer
Director, Breast Medical Oncology
University of Washington School of Medicine
Fred Hutchinson Cancer Research Center
Seattle Cancer Care Alliance
Breast Cancer in Young Women
is a Relatively Rare Disease…
(Hankey et al, JNCI 1994)
…However, Breast Cancer is the Most
Common Cancer in US Women Starting at
Age 30
Top 5 Cancers by Age Group
15-19
20-24
25-29
30-34
35-39
Testis
Testis
Testis
Breast /
Testis
Breast
Hodgkin
Lymphoma
Thyroid
Thyroid
Thyroid
Thyroid
Leukemia
Hodgkin
Lymphoma
Melanoma
Cervix Uteri
Cervix Uteri
Brain and
Other CNS /
Thyroid
Melanoma
Cervix Uteri
Melanoma
Melanoma
Breast
Non-Hodgkin Testis
Lymphoma
Non-Hodgkin Leukemia
Lymphoma
Source: National Cancer Institute, SEER Cancer Statistics Review 1975-2009
Incidence of Breast Cancer in
Young Women
• Over 12,000 women under age 40 are
diagnosed yearly with invasive breast
cancer in the US alone (+2,000 DCIS)
• Tens of thousands more worldwide
(ACS Research, SEER 2008; Porter, N Engl J Med 2008)
Breast Cancer in Young Women
is Different
• Tumor differences
– More ER negative, high grade disease
– More HER-2 positive
• Patient differences
– Biologic
– Psychosocial
How Can We Improve
Breast Cancer Outcomes
in Young Women?
Bridging the Gaps: Current Issues in Medical
Research on Young Women and Breast Cancer
A Basis for Advocacy and Action
Young Survival Coalition White Paper 2001
• Epidemiological Aspects: Incidence of Early Onset
Breast Cancer
• Pathological Aspects: Is Breast Cancer a More
Aggressive Disease in Younger Women?
• Medical Treatment of Younger Women at Risk and
with Breast Cancer
• Diagnostics and Screening Tools for Younger Women
• Ovarian Function: Premature Menopause and
Subsequent Pregnancy after Breast Cancer
Young Survival Coalition Research Think
Tank
February 7-8, 2013
Attendees: Educated advocates and multi-disciplinary
group of medical and research experts
Six groups focused on:
•Risk Factors
•Treatment
•Fertility
•Pregnancy
•Metastases
•Quality of Life
YSC Criteria for Priority Questions
Which research
questions, if answered,
would significantly
impact the quality and
quantity of life for
young women
diagnosed with breast
cancer?
Young Survival Coalition Research Think
Tank
February 7-8, 2013
• Workgroups formulated approximately 60 questions,
based on the current state of the evidence
• Each group presented their recommended top three
goals
• Approx 26 hours of meeting audio files to transcribe
and comb through
• Still a lot of work to do before the new research
agenda is finalized and shared
• Collaboration is key, along with the strategic goal of
focusing on young women
http://www.cancer.gov/cancertopics/aya
Advisory Committee on Breast Cancer in Young
Women
CDC has convened an Advisory Committee on Breast
Cancer in Young Women (ACBCYW), a federal advisory
committee established by the Education and Awareness
Requires Learning Young (EARLY) Act
http://www.cdc.gov/cancer/breast/what_cdc_is_doing/young_women.htm
European School of Oncology Breast Cancer
in Young Women Conference (BCY1)
Dublin, Ireland, November 2012
MAIN TOPICS
• Hereditary breast cancer
• Diagnostic tools in young women
• Local therapy
• Systemic therapy
• Pregnancy and breast cancer
• Fertility preservation
• Psychosocial aspects
• Management of side effects
How Can We Improve Breast
Cancer Outcomes in Young
Women?
•
•
•
•
Prevention
Earlier Detection
Better Treatment
Survivorship and Long-term
Follow-up
How Can We Improve Breast
Cancer Outcomes in Young
Women?
•
•
•
•
Prevention
Earlier Detection
Better Treatment
Survivorship and Long-term
Follow-up
Breast Cancer Risk Factors:
Genetics
Fam ily
15-20% Clusters
Hereditary
5-10%
Sporadic
70-80%
Genes that Cause Hereditary
Susceptibility to Breast Cancer
• BRCA1 and BRCA2
– Breast cancer risk 50 - 85%
» Early onset, 1/2 diagnosed by age 41
» Second primary breast cancer 40 - 60%
» Male breast cancer (BRCA2) 6%
– Ovarian cancer risk 10 - 40%
• TP53 (Li Fraumeni syndrome)
• PTEN (Cowden’s syndrome)
• CHK2
– low penetrance – breast cancer risk doubled?
• Undiscovered genes
UW Laboratory Medicine: New BROCA
Test for Hereditary Cancer Risk
T Walsh, E Swisher, MC King
• Useful for evaluation of patients with suspected
hereditary cancer predisposition, with focus on
syndromes that include breast or ovarian cancer
• Depending on the gene involved, these cancers may
co-occur with other cancer types (colorectal,
endometrial, pancreatic, endocrine, or melanoma)
• If mutations in BRCA1 or BRCA2 are suspected,
these should be evaluated with a separate test
• BROCA uses next-generation sequencing to detect
mutations in 40 genes
• The assay completely sequences all exons and
flanking introns of these genes AND detects large
deletions, duplications, and mosaicism
Breast Cancer Risk Factors:
Lifestyle
Risk Factor
High Risk
Category
Referent Group Relative
Risk
Obesity
> 35 BMI
< 25
1.2-1.5
Physical Activity
Inactive
Regular activity
1.25-1.7
Alcohol Use
>2 drinks/day
Non drinkers
McTiernan, Oncologist 2003; Hamijima, Br J Ca 2002
1.5
Physical Activity and Breast Cancer
Women’s Health Initiative (WHI)
McTiernan A et al, JAMA 2003
• Patients: 74,171 women ages 50-79
– 1,780 cases of breast cancer diagnosed over 5 yrs
• Study: evaluated incidence of breast cancer correlated
to physical activity at age 18, 35, 50
• Results:
– Regular strenuous physical activity at age 35 had
14% reduction in breast cancer risk (similar at age
18, 50)
– 1.25-2.5 hrs/wk brisk walking had 18% decreased
risk
– Greatest reduction seen with >10 hrs/wk brisk
walking
New York Breast Cancer Study: Breast
and Ovarian Cancer Risks in Jewish
Women with BRCA1/2 Mutations
King MC et al, Science 2003
In women with
BRCA1/2
mutations who
developed
breast cancer,
regular exercise
delayed age of
onset by 10
years
Exercise Can Impact Breast Cancer Survival
Exercise and Survival After Breast Cancer
Diagnosis (Nurses Health Study)
Holmes MD et al, JAMA 2005
Patients: 2,987 nurses with early stage breast cancer
Physical activity categories:
– LOW: < 3 MET hours per week
– LOW/MED: 3-8.9 MET hours/week
– MED/HIGH: 9-14.9 MET hours/week
– HIGH: > 24 MET hours/week
(3 MET hours/week equal to walking average pace of 2-3
miles per hour for 1 hour)
• Results: Compared to women with LOW physical activity,
risk of dying of breast cancer was:
– 20% less for LOW/MED exercise
– 40-50% less for MED/HIGH and HIGH exercise (at least 3
hours per week walking at average pace)
Ongoing Study SWOG S1008:Feasibility
Study of a Weight Loss Intervention in Breast
and Colorectal Cancer
Eligibility Criteria:
Female
Age > 21 years
Postmenopausal
Stage I-III breast/colorectal CA
6 - 24 mos post-treatment
BMI > 25 kg/m2
Sedentary
Primary Endpoints (12 months):
• Feasibility in Breast ; Colorectal
• >5% change in weight in Breast;
Colorectal
E
N
R
O
L
L
12 Month Weight Loss Program:
Curves exercise
(goal: 220 min/wk of mod-intense activity)
+
Curves diet (low-fat, high fruit/veg,1500
kcal/d)
+
Telephone-based behavioral counseling
(14 sessions over 12 mos)
Secondary Endpoints:
• Anthropometric measures/ body
composition
• Physical activity
• Diet
• Biomarkers
• Quality of life
• Program acceptability
Breast Cancer Risk Reduction
• Primary Prevention
–Lifestyle
–Chemoprevention
–Prophylactic surgery
Ongoing SWOG S0812: Vitamin D in Premenopausal
Women at High Risk for Breast Cancer (PI: K Crew)
Eligibility:
Premenopausal, Age 18-50
5-yr Gail risk ≥1.67% or
lifetime risk ≥20%
• BRCA1/2, PTEN, p53 mutation
• ADH, ALH, LCIS, DCIS (including
microinvasive and T1a)
 Stage I-II breast CA, >5yrs in
remission
• 25(OH)D ≤32ng/ml
Baseline data collection:
Mammogram
Core breast biopsy
Blood
R
A
N
D
O
M
I
Z
E
Activation: November 2011
Accrual Goal: 200
Cholecalciferol (vit D3)
20,000 IU weekly x 1yr
Vitamin D3 600 IU qd
Matching placebo
x 1yr
Follow-up data collection:
Mammogram
Core breast biopsy
Blood
Primary Endpoint: Change in mammographic density
Secondary Endpoints: Serum and tissue-based biomarkers, toxicity
Ongoing Phase II Low Dose Tamoxifen in
Lymphoma Survivors for Breast Cancer Risk
Reduction
Eligibility:
PI: M Palomares
•childhood and young
adult cancer survivors
treated with chest
radiation
Baseline data collection:
Mammogram
Core breast biopsy
Blood
R
A
N
D
O
M
I
Z
E
Tamoxifen 5 mg daily x 2 yrs
Placebo x 2 yrs
Follow-up data collection:
Mammogram
Core breast biopsy
Blood
Primary Endpoint: Change in mammographic density
Secondary Endpoints: Serum and tissue-based biomarkers, toxicity
How Can We Improve Breast
Cancer Outcomes in Young
Women?
•
•
•
•
Prevention
Earlier Detection
Better Treatment
Survivorship and Long-term
Follow-up
Young Women Present with
More Advanced Disease
• Delays in diagnosis
– Lack of reliable screening
– Lack of awareness of risk or difficult to diagnose:
» “Too young for breast cancer”
» breast cancer during pregnancy
– Access to care issues
Diagnosis and imaging
for staging and follow-up
Diagnosis, imaging and staging in young women should
follow standard algorithms
Consideration should be given to breast MRI in young
women, particularly in the setting of very dense breast
tissue or a genetic predisposition to the disease
For BRCA 1/2 mutation carriers and others at extremely
high risk based on family history or predisposing
mutations in other genes, and for those at increased
risk because of therapeutic radiation in adolescence,
annual surveillance is recommended
Early Detection of Breast Cancer:
The Controversy Around Breast Imaging
Mammogram
Ultrasound
• Magnetic
Resonance Imaging
(MRI)
Mammography is Less
Sensitive in Younger Women
• Screening
mammograms miss
up to 25% of breast
cancers in women in
their 40s, compared
to 10% of cancers for
older women
• Digital (vs film)
mammography may
be better for younger
women and women
with dense breasts
A Newly Recognized Breast Cancer
Risk Factor: Mammographic Density
Several states have now mandated reporting of high breast density
as seen on mammograms to both patient and primary care provider
American Cancer Society
Recommendations for Breast
Cancer Screening 2013
• Mammography: Annually beginning at age 40
and continuing as long as the woman is in
good health
• Health Professional’s Exam: About every 3
years between 20-39, then annually
• Self-Exam: An option for women beginning at
about age 20
• MRI: Women at high risk (> 20% lifetime)
should get a mammogram and MRI yearly.
Women at moderately increased risk (15-20%)
should talk with their health care providers
about MRI screening.
Breast Screening in Young Women with
Hereditary Risk for Breast Cancer
Kriege M et al, NEJM 2004
• Patients: 1,909 Dutch women with elevated risk of breast cancer
– average age 40 years; 358 BRCA1/2 +
• Screening: Clinical breast exam every 6 months, mammography
and MRI yearly
100
90
80
70
60
%
50
40
30
20
10
0
• Results (3 years): 51
tumors detected
Exam
Mammo
MRI
sensitivity
specificity
Breast MRI is better at
detecting cancer than
mammogram in high
risk women, but has a
higher rate of “false
positives”
How Can We Improve Breast
Cancer Outcomes in Young
Women?
•
•
•
•
Prevention
Earlier Detection
Better Treatment
Survivorship and Long-term
Follow-up
Should Treatments be Different in
Young Women with Breast
Cancer?
General Statements
Young age by itself should not be the reason to prescribe
more aggressive therapy then general
recommendations
Both in early and advanced settings, choice of treatment
should include the biological characteristics of the
tumour (ER/PR, HER-2, proliferation, grade), tumor
stage, hormonal milieu*, and patient's comorbidities
* Young does not always mean pre-menopausal
Fertility preservation
Before any treatment decision, young women must be
advised to have fertility and contraception specialized
counselling
Genomic Profiling of Cancer:
Breast Cancer is NOT One Disease!
Multiple breast cancer subtypes
Luminal Luminal HER-2+Basal
Normal
Subtypes vary with
Subtype A Subtype B
Subtype Breast–like
respect to:
• Likelihood of
recurrence
• Sites of metastases
• Response to
treatment
Sorlie et al, Proc Natl Acad Sci
• Frequency of
subtypes varies
across populations
–additional
subtypes likely
exist
What’s the Latest?
Triple Negative Breast Cancer is
a Highly Diverse Group of Cancers
6 subtypes of TNBC identified by gene expression
array!
Lehmann BD, et al. J Clin Invest 121:2750-67, 2011
Endocrine Therapy
Estrogen Receptor and Breast
Cancer
Aromatase
inhibitors,
ovarian
suppression
Estrogen
Estrogen
Receptor
SERMS (tamoxifen)
SERDS (fulvestrant)
Cell
Growth
and
Division
ATLAS: Adjuvant Tamoxifen
Longer Against Shorter (5 vs 10
Years)
• Patients: 6846 women with breast cancer completing 5
years of tamoxifen
– 54% node-negative
– Analysis only includes documented ER+ patients
• Randomized to continue tamoxifen to year 10, or stop
at year 5
• Reporting on 8 yrs median follow-up: compliance,
recurrence, death
Davies C et al. Presented at SABCS 2012, Abstract number S1-2
ATLAS: Adjuvant Tamoxifen Longer
Against Shorter (5 vs 10 Years)
Recurrence
Overall
mortality
Breast cancer
mortality
5 years
617 events
21.4%
639 events
12.2%
10 years
711 events
25.1%
722 events
15%
P=0.002
331 events
397 events
P=0.01
Compliance after 2 years 80%
Davies C et al. Presented at SABCS 2012, Abstract number S1-2
P value
P=0.01
ATLAS: Adjuvant Tamoxifen Longer
Against Shorter (5 vs 10 Years)
• Only had access to toxicity related to
hospitalization or death
• Toxicities for 10 vs 5 years tamoxifen (from
Lancet publication: Davies C et al, Lancet 2012,
epub ahead of print)
– Pulmonary embolus HR 1.87 p=0.01
– Stroke HR 1.06 (ns)
– Ischemic heart disease HR 0.76 p=0.02
– Endometrial cancer HR 1.74 p=0.0002 (3.1%
vs 1.6%)
Davies C et al. Presented at SABCS2012, Abstract number S1-2
ATLAS: Adjuvant Tamoxifen Longer
Against Shorter (5 vs 10 Years)
How to incorporate into practice:
• Weighing risks vs benefits
• Need to estimate woman’s residual risk of recurrence after 5
years of tamoxifen
• Half of deaths NOT breast cancer related!
• Really only applicable in premenopausal women
• AIs standard in postmenopausal
• For women who have become postmenopausal while on
tamoxifen, consider AI (ie NCIC MA17 study)
• Patient acceptance
• QOL issues on tamoxifen (hot flashes, night sweats,
insomnia)
• Generalizability to other endocrine agents (longer duration AIs)?
Davies C et al. Presented at SABCS2012, Abstract number S1-2
Ongoing IBCSG 24-02: Suppression
of Ovarian Function Trial (SOFT)
PI: A. Goldhirsch
•Does ovarian function suppression add to the standard in
premenopausal women (tamoxifen)?
•Is an aromatase inhibitor of added benefit in premenopausal
women when the ovaries are suppressed?
Premenopausal, ER+,
ovarian function intact after
chemo or no chemo
Tamoxifen
vs.
Tamoxifen + OFS
vs.
Exemestane (Aromasin) + OFS
ABCSG-012: Adjuvant Hormonal Therapy in
Premenopausal Breast Cancer Patients
Gnant M et al, NEJM 360, 2009
1800 premenopausal women with ER+ early
breast cancer
Goserelin 3 years
(ovarian suppression)
Anastrozole (Arimidex)
Zoledronic acid
4mg q6 mo
Control
Tamoxifen
Zoledronic acid
4mg q6 mo
Control
ABCSG-12 Trial of Endocrine Therapy
Gnant M et al, NEJM 360, 2009
47.8 months
median follow-up
Tamoxifen Anastrozole
HR
P
Value
(n = 900)
(n = 903)
Disease-Free
Survival
65 events
72 events
1.096
.593
Overall Survival
15 events
27 events
1.791
.065
•Conclusion: No difference between tamoxifen and
anastrozole
•A trend towards tamoxifen being better?
Can Bisphosphonates Prevent Cancer Recurrences?
ABCSG-12: Premenopausal Breast Cancer Pts
Receiving Adjuvant Hormonal Rx
Gnant M et al, N Engl J Med 360:679-691, 2009
100
90
80
80
70
DFS
60
50
40
30
No of Hazard Ratio (95% CI)
Events
vs No ZOL
P Value
ZOL
54
0.64 (0.46 to 0.91)
.01
No ZOL 83
20
10
0
0
12
24
36
48
60
72
Time since Randomization, months
84
35% reduction in recurrences from
adding zoledronic acid – but very
few recurrences!
First Event per Patient, n
Disease-Free Survival, %
90
2
10
70
10
Death without prior recurrence
Secondary malignancy
Contralateral breast cancer
Distant recurrence
Locoregional recurrence
60
0
9
50
40
41
6
30
29
20
10
20
10
0
(n = 904)
No ZOL
(n = 899)
ZOL
Median follow-up = 48 months
Chemotherapy: THE PAST
2000 NCI Consensus Development Conference
on Adjuvant Breast Cancer
Chemotherapy should be offered to the
majority of women with early stage
breast cancer regardless of size, lymph
node, menopausal or hormone receptor
status
Chemotherapy: THE PRESENT AND
FUTURE
Individualizing Estimates of Recurrence
Risk and Chemotherapy Benefit from
Therapy Using
Genomic/Molecular Profiling
Who Doesn’t Need Chemotherapy?
Large Benefit of Chemotherapy in
Young Women
(EBCTCG, Lancet, 1998)
Interventions to Reduce Risk of
Chemotherapy Toxicity
SWOG S0230: Study of GnRH Analogue to
Reduce Ovarian Dysfunction in Young
Women Undergoing Chemotherapy
PI: H Moore
• Eligibility: 458 premenopausal ER/PR-negative
stage I-III breast cancer patients receiving standard
chemotherapy
• Treatment:
– Randomized to receive ovarian suppression
with goserelin with each chemo cycle versus no
ovarian suppression
• Endpoints: Ovarian failure at 2 years (6 months
amenorrhea with elevated FSH)
As of Yesterday, Four FDA-Approved
Drugs with HER-2 as a Target
Pertuzumab
Anti-HER-2 Antibody
HER-2
Trastuzumab (Herceptin)
Anti-HER-2 Antibody
cancer cell
nucleus
T-DM1
Antibody-Drug
Conjugate
Lapatinib (Tykerb)
Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
cell division
Approved Yesterday: Trastuzumab-DM1 (TDM1)
Trastuzumab
Mertansine: anti-tubulin
Identifying Additional Targets in the
Treatment of Breast Cancer
Metastasis
Inhibitors
AntiAngiogenesis
EGFR
Inhibitors
HER-2
Inhibitors
mTOR
Inhibitors
IGF-R
Inhibitors
MUC-1
Antibodies
Src
Inhibitors
Farnesyl
Transferase
MEK
HIF
Cell Cycle Inhibitors
Inhibitors
Inhibitors
Inhibitors
Aurora Kinase
HSP90
Inhibitors
Inhibitors
Raf
Pro-apoptotic
Inhibitors
Drugs
Proteosome
Mdm2
Kinesins
Inhibitors
Inhibitors
HDAC
TubulinInhibitors
interacting
Death
Agents
Receptors
Courtesy of D. Budman
How Can We Improve Breast
Cancer Outcomes in Young
Women?
•
•
•
•
Prevention
Earlier Detection
Better Treatment
Survivorship and Long-term
Follow-up
Early Breast Cancer
In view of the long potential life-time, particular attention
should be paid to possible long-term toxicities of
adjuvant treatments
Long-term/Late Effects of Diagnosis and
Treatment are Different for Younger Women
• Longer-term effects
» Very premature menopause
• Infertility, family planning
• Osteoporosis
• Cognitive Function
• Cardiovascular health
• Weight gain
» Implications for second cancers
• Genetic issues
• Screening issues (breast MRI?)
Psychosocial Distress in Young
Breast Cancer Survivors
• Young women are more likely to be concerned about:
– Role functioning at home and/or work
– Beauty and attractiveness
– Sexual functioning
– Fertility and family planning
Breast cancer and pregnancy
All retrospective available data report not only no
detrimental effect of a subsequent pregnancy on breast
cancer outcome
Therefore, pregnancy after breast cancer should not in
principle be discouraged
Prospective definitive data from clinical trials should be
collected
Concluding Statement
•Many specific issues in the treatment of young
women with breast cancer, both in early and
advanced settings, still lack definitive proven
standards
•Therefore, well-designed, independent,
prospective randomized trials should be a global
research priority
Breast Cancer in Young Women: Summary
• The experience of breast cancer differs by age at
diagnosis
• Young age may not be an independent predictor
of outcome in all disease subtypes
• Targeting the tumor in consideration of the host
(including psychosocial concerns) is most
prudent
• Good news: increasing awareness is leading to
focused research and comprehensive care
approaches that may improve both breast cancer
and psychosocial outcomes