Young Women and Breast Cancer: The Future of Care Julie R. Gralow, M.D. Jill Bennett Endowed...
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Transcript of Young Women and Breast Cancer: The Future of Care Julie R. Gralow, M.D. Jill Bennett Endowed...
Young Women and Breast Cancer: The Future of Care
Julie R. Gralow, M.D.Jill Bennett Endowed Professor of Breast Cancer
Director, Breast Medical OncologyUniversity of Washington School of Medicine
Fred Hutchinson Cancer Research CenterSeattle 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
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
Non-Hodgkin Lymphoma
Leukemia Breast Non-Hodgkin Lymphoma
Testis
Source: National Cancer Institute, SEER Cancer Statistics Review 1975-2009
Top 5 Cancers by Age Group
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 ActionYoung 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
http://www.cdc.gov/cancer/breast/what_cdc_is_doing/young_women.htm
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
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
Sporadic
Hereditary
FamilyClusters15-20%
5-10%
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 1.5
McTiernan, Oncologist 2003; Hamijima, Br J Ca 2002
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 MutationsKing 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 cancerPhysical 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 CancerEligibility Criteria: Female Age > 21 years Postmenopausal Stage I-III breast/colorectal CA 6 - 24 mos post-treatment BMI > 25 kg/m2
Sedentary
ENROLL
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)
Primary Endpoints (12 months): •Feasibility in Breast ; Colorectal•>5% change in weight in Breast; Colorectal
Secondary Endpoints: •Anthropometric measures/ body composition•Physical activity•Diet•Biomarkers•Quality of life•Program acceptability
• Primary Prevention–Lifestyle–Chemoprevention–Prophylactic surgery
Breast Cancer Risk Reduction
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
RANDOMIZE
Cholecalciferol (vit D3)20,000 IU weekly x 1yr
Matching placebox 1yr
Baseline data collection: Follow-up data collection:Mammogram MammogramCore breast biopsy Core breast biopsyBlood Blood
Primary Endpoint: Change in mammographic densitySecondary Endpoints: Serum and tissue-based biomarkers, toxicity
Vitamin D3 600 IU qd
Activation: November 2011Accrual Goal: 200
Ongoing Phase II Low Dose Tamoxifen in Lymphoma Survivors for Breast Cancer Risk
ReductionPI: M Palomares
Eligibility:• childhood and young
adult cancer survivors treated with chest radiation
RANDOMIZE
Tamoxifen 5 mg daily x 2 yrs
Placebo x 2 yrs
Baseline data collection: Follow-up data collection:Mammogram MammogramCore breast biopsy Core breast biopsyBlood Blood
Primary Endpoint: Change in mammographic densitySecondary 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
• Results (3 years): 51 tumors detected
0102030405060708090
100
sensitivity specificity
Exam
Mammo
MRI
%
• 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
Breast MRI is better at detecting cancer thanmammogram 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?
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
General Statements
Before any treatment decision, young women must be advised to have fertility and contraception specialized counselling
Fertility preservation
Genomic Profiling of Cancer: Breast Cancer is NOT One Disease!
Multiple breast cancer subtypes
Luminal Subtype A
Luminal Subtype B
HER-2+Basal Subtype
Normal Breast–like
Sorlie et al, Proc Natl Acad Sci 100:8418, 2003
Subtypes vary with respect to:
• Likelihood of recurrence
• Sites of metastases
• Response to treatment
• 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
Lehmann BD, et al. J Clin Invest 121:2750-67, 2011
6 subtypes of TNBC identified by gene expression array!
Endocrine TherapyEstrogen Receptor and Breast
Cancer
Estrogen
Cell Growth
and Division
Estrogen Receptor
SERMS (tamoxifen)
SERDS (fulvestrant)
Aromatase inhibitors,
ovarian suppression
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)
Davies C et al. Presented at SABCS 2012, Abstract number S1-2
5 years 10 years P value
Recurrence 617 events21.4%
711 events25.1% P=0.002
Overall mortality
639 events12.2%
722 events15% P=0.01
Breast cancer mortality 331 events 397 events P=0.01
Compliance after 2 years 80%
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)
Davies C et al. Presented at SABCS2012, Abstract number S1-2
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)?
Ongoing IBCSG 24-02: Suppression of Ovarian Function Trial (SOFT)
PI: A. Goldhirsch
Premenopausal, ER+,ovarian function intact after
chemo or no chemo
Tamoxifen vs.
Tamoxifen + OFSvs.
Exemestane (Aromasin) + OFS
• 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?
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
Anastrozole (Arimidex)
Goserelin 3 years (ovarian suppression)
Tamoxifen
Zoledronic acid
4mg q6 mo
Control Zoledronic acid
4mg q6 mo
Control
ABCSG-12 Trial of Endocrine TherapyGnant M et al, NEJM 360, 2009
ABCSG-12 Trial of Endocrine TherapyGnant M et al, NEJM 360, 2009
Tamoxifen
(n = 900)
Anastrozole
(n = 903)HR P
Value
Disease-Free Survival 65 events 72 events 1.096 .593
Overall Survival 15 events 27 events 1.791 .065
47.8 months median follow-up
• 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 RxGnant M et al, N Engl J Med 360:679-691, 2009
Median follow-up = 48 months
100
90
80
70
60
50
40
30
20
10
00 12 24 36 48 60 72 84
Time since Randomization, months
Dis
ease
-Fre
e Su
rviv
al, %
No of Hazard Ratio (95% CI)Events vs No ZOLP Value
ZOL 54 0.64 (0.46 to 0.91).01
No ZOL 83
DFS
10
41
29
10
6
10
9
2
0
20
0
10
20
30
40
50
60
70
80
90
No ZOL ZOL
Death without prior recurrence
Secondary malignancy
Contralateral breast cancer
Distant recurrence
Locoregional recurrence
Fir
st E
ven
t p
er P
atie
nt,
n
(n = 904) (n = 899)
35% reduction in recurrences from adding zoledronic acid – but very few recurrences!
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 ChemotherapyPI: 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
cell division
HER-2
nucleus
cancer cell
Trastuzumab (Herceptin) Anti-HER-2 Antibody
Lapatinib (Tykerb) Dual HER-1/HER-2 Tyrosine Kinase Inhibitor
Pertuzumab Anti-HER-2 Antibody
T-DM1Antibody-Drug Conjugate
Approved Yesterday: Trastuzumab-DM1 (T-DM1)
Trastuzumab
Mertansine: anti-tubulin
Identifying Additional Targets in the Treatment of Breast Cancer
Death Receptors
Courtesy of D. Budman
Tubulin-interacting
Agents
HDAC Inhibitors
Metastasis Inhibitors
Anti-Angiogenesis
HER-2 Inhibitors IGF-R
Inhibitors MUC-1 Antibodies
Proteosome Inhibitors
mTOR Inhibitors Farnesyl
Transferase Inhibitors
Mdm2 Inhibitors
Pro-apoptotic Drugs
Kinesins
Aurora Kinase Inhibitors
MEK InhibitorsHIF
Inhibitors
Raf Inhibitors
EGFR Inhibitors
HSP90 Inhibitors
Src Inhibitors
Cell Cycle Inhibitors
How Can We Improve Breast Cancer Outcomes in Young
Women?
• Prevention• Earlier Detection• Better Treatment• Survivorship and Long-term
Follow-up
In view of the long potential life-time, particular attention should be paid to possible long-term toxicities of adjuvant treatments
Early Breast Cancer
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
• 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
Concluding Statement
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