1. 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

2. Breast Cancer in Young Women is a Relatively Rare Disease…
(Hankey et al, JNCI 1994)

3. Top 5 Cancers by Age Group
…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
Breast / Testis
Breast
Hodgkin Lymphoma
Thyroid
Leukemia
Melanoma
Cervix Uteri
Brain and Other CNS / Thyroid
Non-Hodgkin Lymphoma
Source: National Cancer Institute, SEER Cancer Statistics Review

4. 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)

5. Breast Cancer in Young Women is Different
Tumor differences
More ER negative, high grade disease
More HER-2 positive
Patient differences
Biologic
Psychosocial

7. How Can We Improve Breast Cancer Outcomes in Young Women?

8. 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

9. 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

10. 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?

11. 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

12. Advisory Committee on Breast Cancer in Young Women
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

13. 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

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

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

16. Breast Cancer Risk Factors: Genetics
15-20%
5-10%
70-80%

17. Genes that Cause Hereditary Susceptibility to Breast Cancer
BRCA1 and BRCA2
Breast cancer risk %
Early onset, 1/2 diagnosed by age 41
Second primary breast cancer %
Male breast cancer (BRCA2) 6%
Ovarian cancer risk %
TP53 (Li Fraumeni syndrome)
PTEN (Cowden’s syndrome)
CHK2
low penetrance – breast cancer risk doubled?
Undiscovered genes

18. 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

19. Breast Cancer Risk Factors: Lifestyle
High Risk Category
Referent Group
Relative Risk
Obesity
> 35 BMI
< 25
Physical Activity
Inactive
Regular activity
Alcohol Use
>2 drinks/day
Non drinkers
1.5
McTiernan, Oncologist 2003; Hamijima, Br J Ca 2002

20. 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)
hrs/wk brisk walking had 18% decreased risk
Greatest reduction seen with >10 hrs/wk brisk walking

21. 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

22. 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: MET hours/week
MED/HIGH: 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)

23. Ongoing Study SWOG S1008:Feasibility Study of a Weight Loss Intervention in Breast and Colorectal Cancer E N R O L
Eligibility Criteria:
Female
Age > 21 years
Postmenopausal
Stage I-III breast/colorectal CA
mos post-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

24. Breast Cancer Risk Reduction
Primary Prevention
Lifestyle
Chemoprevention
Prophylactic surgery

25. 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

26. Ongoing Phase II Low Dose Tamoxifen in Lymphoma Survivors for Breast Cancer Risk Reduction PI: 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
Blood Blood
Primary Endpoint: Change in mammographic density
Secondary Endpoints: Serum and tissue-based biomarkers, toxicity

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

28. 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

29. 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

30. Early Detection of Breast Cancer: The Controversy Around Breast Imaging
Mammogram
Ultrasound
Magnetic Resonance Imaging (MRI)

31. 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

32. 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

33. 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.

34. 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
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”

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

36. Should Treatments be Different in Young Women with Breast Cancer?

37. 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

38. Fertility preservation
Before any treatment decision, young women must be advised to have fertility and contraception specialized counselling

39. Genomic Profiling of Cancer: Breast Cancer is NOT One Disease
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
A total of 115 breast cancer tumor tissues and 7 nonmalignant tissues were analyzed for characteristic patterns of gene expression measured by DNA microarrays applicable to classifying tumors into clinically relevant subgroups. Analysis was by hierarchical clustering based on patterns of expression of 534 “intrinsic” genes, delineated relative to 5 tissue subtypes:
One basal-like, 1 ErbB2 (HER2)-overexpressing (ERBB2+), 2 luminal-like (subtypes A and B), and 1 normal breast tissue–like
Slide shows the 5 recognized subgroups of coexpressed genes, with group C representing the ErbB2 (HER2)-overexpressing subgroup of genes.
Expression of the HER2 gene cluster is most pronounced in the ERBB2+ tissue subtype of tumors, hence its designation.
Results strongly support the contention that many breast cancer subtypes represent biologically distinct disease entities.
Sorlie et al, Proc Natl Acad Sci 100:8418, 2003
Sørlie et al. Proc Natl Acad Sci U S A. 2003;100:8418.

40. 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: , 2011

41. Estrogen Receptor and Breast Cancer
Endocrine Therapy
Estrogen Receptor and Breast Cancer
Aromatase inhibitors, ovarian suppression
Cell Growth and Division
Estrogen
Estrogen Receptor
SERMS (tamoxifen)
SERDS (fulvestrant)

42. 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

43. ATLAS: Adjuvant Tamoxifen Longer Against Shorter (5 vs 10 Years)
P value
Recurrence
617 events
21.4%
711 events
25.1%
P=0.002
Overall mortality
639 events
12.2%
722 events
15%
P=0.01
Breast cancer mortality
331 events
397 events
Compliance after 2 years 80%
Davies C et al. Presented at SABCS 2012, Abstract number S1-2

44. 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 p=0.02
Endometrial cancer HR 1.74 p= (3.1% vs 1.6%)
Davies C et al. Presented at SABCS2012, Abstract number S1-2

45. 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

46. ovarian function intact after Exemestane (Aromasin) + OFS
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
Exemestane (Aromasin) + OFS

47. 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)
The ABCSG study 12 is a randomised trial that has been designed to investigate the efficacy and tolerability of goserelin (3.6 mg every 28 days for 3 years) combined with either anastrozole (1 mg per day for 3 years) or tamoxifen (20 mg per day for 3 years) in postmenopausal women with hormone-responsive early breast cancer.
Patients are further randomised to treatment with bisphosphonate (zoledronate) or control.
Anastrozole (Arimidex)
Tamoxifen
Zoledronic acid
4mg q6 mo
Control
Zoledronic acid
4mg q6 mo
Control

48. ABCSG-12 Trial of Endocrine Therapy Gnant M et al, NEJM 360, 2009
47.8 months median follow-up
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
Conclusion: No difference between tamoxifen and anastrozole
A trend towards tamoxifen being better?

49. Can Bisphosphonates Prevent Cancer Recurrences
Can Bisphosphonates Prevent Cancer Recurrences? ABCSG-12: Premenopausal Breast Cancer Pts Receiving Adjuvant Hormonal Rx Gnant M et al, N Engl J Med 360: , 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 (0.46 to 0.91) .01
No ZOL 83 20 10 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 49

50. 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

51. Chemotherapy: THE PRESENT AND FUTURE Individualizing Estimates of Recurrence Risk and Chemotherapy Benefit from Therapy Using Genomic/Molecular Profiling Who Doesn’t Need Chemotherapy?

52. Large Benefit of Chemotherapy in Young Women
(EBCTCG, Lancet, 1998)

53. 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)

54. 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

55. Approved Yesterday: Trastuzumab-DM1 (T-DM1)
The trastuzumab-mertansine drug conjugate efficiently delivers a chemotherapeutic drug to HER2 positive breast cancer cells by encompassing three components (drug, linker, and antibody).
The unique chemical linker, MCC, is conjugated via lysine side chains to the cytotoxic agent, mertansine, and is designed to provide a stable antibody-drug bond that preserves the binding activity of trastuzumab to the extracellular domain of HER2.
Conjugation of the highly cytotoxic mertansine to a HER2 specific monoclonal antibody is an important approach to confer selectivity to mertansine and potentially increases the therapeutic index.
Trastuzumab
Mertansine: anti-tubulin

56. 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

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

58. Early Breast Cancer
In view of the long potential life-time, particular attention should be paid to possible long-term toxicities of adjuvant treatments

59. 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?)

60. 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

62. 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

65. 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

66. 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