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