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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.

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young women and breast cancer the future of care
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

however breast cancer is the most common cancer in us women starting at age 30
…However, Breast Cancer is the Most Common Cancer in US Women Starting at Age 30

Top 5 Cancers by Age Group

Source: National Cancer Institute, SEER Cancer Statistics Review 1975-2009

incidence of breast cancer in young women
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 w omen is different
Breast Cancer in Young Women is Different
  • Tumor differences
    • More ER negative, high grade disease
    • More HER-2 positive
  • Patient differences
    • Biologic
    • Psychosocial
slide8

Bridging the Gaps: Current Issues in Medical Research on Young Women and Breast CancerA 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
Young Survival Coalition Research Think TankFebruary 7-8, 2013
  • Attendees: Educated advocates and multi-disciplinary group of medical and research expertsSix 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?

YSC Criteria for Priority Questions
young survival coalition research think tank february 7 8 20131
Young Survival Coalition Research Think TankFebruary 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
slide12

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

slide13

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 women1
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 women2
How Can We Improve Breast Cancer Outcomes in Young Women?
  • Prevention
  • Earlier Detection
  • Better Treatment
  • Survivorship and Long-term Follow-up
genes that cause hereditary susceptibility to breast cancer
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
UW Laboratory Medicine: New BROCA Test for Hereditary Cancer RiskT 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
slide19

Breast Cancer Risk Factors: Lifestyle

McTiernan, Oncologist 2003; Hamijima, Br J Ca 2002

physical activity and breast cancer women s health initiative whi mctiernan a et al jama 2003
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
slide21
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

slide22

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)
slide23

Ongoing Study SWOG S1008:Feasibility Study of a Weight Loss Intervention in Breast and Colorectal Cancer

E

N

R

O

L

L

Eligibility Criteria:

Female

Age > 21 years

Postmenopausal

Stage I-III breast/colorectal CA

6 - 24 mospost-treatment

BMI > 25 kg/m2

Sedentary

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
  • Primary Endpoints (12 months):
  • Feasibility in Breast ; Colorectal
  • >5% change in weight in Breast; Colorectal
slide24

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
Ongoing SWOG S0812: Vitamin D in Premenopausal Women at High Risk for Breast Cancer (PI: K Crew)

Activation: November 2011

Accrual Goal: 200

  • 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

R

A

N

D

O

M

I

Z

E

Cholecalciferol (vit D3)

20,000 IU weekly x 1yr

Matching placebo

x 1yr

Vitamin D3 600 IU qd

Baseline data collection: Follow-up data collection:

Mammogram Mammogram

Core breast biopsy Core breast biopsy

Blood Blood

Primary Endpoint: Change in mammographic density

Secondary Endpoints: Serum and tissue-based biomarkers, toxicity

slide26
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

R

A

N

D

O

M

I

Z

E

Tamoxifen 5 mg daily x 2 yrs

Placebo x 2 yrs

Baseline data collection: Follow-up data collection:

Mammogram Mammogram

Core breast biopsy Core breast biopsy

BloodBlood

Primary Endpoint: Change in mammographic density

Secondary Endpoints: Serum and tissue-based biomarkers, toxicity

how can we improve breast cancer outcomes in young women3
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
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

Diagnosis and imaging for staging and follow-up

early detection of breast cancer the controversy around breast imaging
Early Detection of Breast Cancer: The Controversy Around Breast Imaging

Mammogram

  • Ultrasound
  • Magnetic Resonance Imaging (MRI)
mammography is less sensitive in younger women
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
slide32

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
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

%

Breast Screening in Young Women with Hereditary Risk for Breast CancerKriege 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
  • Results (3 years): 51 tumors detected

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 women4
How Can We Improve Breast Cancer Outcomes in Young Women?
  • Prevention
  • Earlier Detection
  • Better Treatment
  • Survivorship and Long-term Follow-up
slide37

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

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
Genomic Profiling of Cancer: Breast Cancer is NOT One Disease!Multiple breast cancer subtypes

Luminal Subtype A

Luminal Subtype B

Basal Subtype

Normal Breast–like

HER-2+

  • Subtypes vary with respect to:
  • Likelihood of recurrence
  • Sites of metastases
  • Response to treatment
  • Frequency of subtypes varies across populations –additional subtypes likely exist

Sorlie et al, Proc NatlAcadSci 100:8418, 2003

what s the latest triple negative breast cancer is a highly diverse group of cancers
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

slide41

Endocrine Therapy

Estrogen Receptor and Breast Cancer

Aromatase inhibitors, ovarian suppression

Cell Growth and Division

Estrogen

Estrogen Receptor

SERMS (tamoxifen)

SERDS (fulvestrant)

atlas adjuvant tamoxifen longer against shorter 5 vs 10 years
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 years1
ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years)

Compliance after 2 years 80%

Davies C et al. Presented at SABCS 2012, Abstract number S1-2

atlas adjuvant tamoxifen longer against shorter 5 vs 10 years2
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 years3
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
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

slide47

ABCSG-012: Adjuvant Hormonal Therapy in PremenopausalBreast Cancer Patients

Gnant M et al, NEJM 360, 2009

1800 premenopausal women with ER+ early breast cancer

Goserelin 3 years (ovarian suppression)

Anastrozole (Arimidex)

Tamoxifen

Zoledronic acid

4mg q6 mo

Control

Control

Zoledronic acid

4mg q6 mo

slide48

ABCSG-12 Trial of Endocrine TherapyGnant M et al, NEJM 360, 2009

47.8 months median follow-up

  • Conclusion: No difference between tamoxifen and anastrozole
  • A trend towards tamoxifen being better?
slide49

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

100

90

80

70

DFS

60

50

Disease-Free Survival, %

First Event per Patient, n

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

84

Time since Randomization, months

(n = 904)

(n = 899)

35% reduction in recurrences from adding zoledronic acid – but very few recurrences!

Median follow-up = 48 months

chemotherapy the past 2000 nci consensus development conference on adjuvant breast cancer
Chemotherapy: THE PAST2000 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

slide51

Chemotherapy: THE PRESENT AND FUTUREIndividualizing Estimates of Recurrence Risk and Chemotherapy Benefit from Therapy Using Genomic/Molecular ProfilingWho Doesn’t Need Chemotherapy?

slide53

Interventions to Reduce Risk of Chemotherapy ToxicitySWOG 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
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

Lapatinib (Tykerb)

Dual HER-1/HER-2 Tyrosine Kinase Inhibitor

T-DM1

Antibody-Drug Conjugate

cell division

approved yesterday trastuzumab dm1 t dm1
Approved Yesterday: Trastuzumab-DM1 (T-DM1)

Trastuzumab

Mertansine: anti-tubulin

identifying additional targets in the treatment of breast cancer
Identifying Additional Targets in the Treatment of Breast Cancer

HER-2 Inhibitors

Metastasis Inhibitors

IGF-R Inhibitors

EGFR Inhibitors

MUC-1 Antibodies

Anti-Angiogenesis

Src Inhibitors

mTOR Inhibitors

Farnesyl Transferase Inhibitors

MEK Inhibitors

HIF Inhibitors

Cell Cycle Inhibitors

Aurora Kinase Inhibitors

HSP90 Inhibitors

Raf Inhibitors

Pro-apoptotic Drugs

Proteosome Inhibitors

Mdm2 Inhibitors

Kinesins

HDAC Inhibitors

Tubulin-interacting Agents

Death Receptors

Courtesy of D. Budman

how can we improve breast cancer outcomes in young women5
How Can We Improve Breast Cancer Outcomes in Young Women?
  • Prevention
  • Earlier Detection
  • Better Treatment
  • Survivorship and Long-term Follow-up
early breast cancer

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 w omen
Long-term/Late Effects of Diagnosis and Treatment are Different for Younger Women
  • Longer-termeffects
      • 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 b reast c ancer s urvivors
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

Breast cancer and pregnancy

slide65

ConcludingStatement

  • 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
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