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Young Women and Breast Cancer: The Future of Care

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Presentation on theme: "Young Women and Breast Cancer: The Future of Care"— Presentation transcript:

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

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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

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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

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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


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