BREAST CANCER RISK REDUCTION Clinical Practice Guideline Update © American Society of Clinical Oncology®.

BREAST CANCER RISK REDUCTION

Clinical Practice Guideline Update

www.asco.org/guidelines/ © American Society of Clinical Oncology®. All rights reserved.

http://www.asco.org/guidelines/

Introduction•ASCO published its first breast cancer risk reduction (BCRR) guideline in 1999

•ASCO Guidelines are updated at intervals by an Update Committee of the original Expert Panel

• BCRR updates published in 2002 and 2009



Guideline Methodology:Systematic Review

•Literature review focused on available systematic reviews and meta-analyses of published phase III randomized controlled trials (RCTs) on breast cancer risk reduction from June 2007 through June 2012

• MEDLINE

• Cochrane Collaboration Library



Clinical Questions

•Which pharmacologic interventions reduce the risk of developing breast cancer in women not previously diagnosed with breast cancer?



Recommendations: Tamoxifen•Should be discussed as an option to reduce the risk of invasive BC, specifically estrogen (ER)-positive breast cancer, in premenopausal women who are ≥ 35 years of age with a 5-year projected absolute BC risk ≥ 1.66%, or with LCIS. Risk reduction benefit continues for at least 10 years.

•Should be discussed as an option to reduce the risk of invasive BC, specifically estrogen (ER)-positive breast cancer, in postmenopausal women who are ≥ 35 years of age with a 5-year projected absolute BC risk ≥ 1.66%, or with LCIS. Risk reduction benefit continues for at least 10 years.



Recommendations: Tamoxifen•Is not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization. •Is not recommended in combination with hormone therapy.•Is not recommended for women who are pregnant, women who may become pregnant, or nursing mothers.•Follow-up should include a timely work-up of abnormal vaginal bleeding. •Discussions with patients and health care providers should include both the risks and benefits of tamoxifen in the preventive setting.•DOSAGE: 20 mg/d orally for 5 years.



Results from SERM Trials:Tamoxifen vs. placebo


NSABP-P1 IBIS-I ITALIAN ROYAL MARSDENFollow-up (years) 7 (mean 6.2) 10 (median 8.0) 13 (median, 11.2) 20 (median, 13.2)

BREAST CANCER INCIDENCE

Sample size* TAM 6597 3579 2700 1238

PLA 6610 3575 2708 1233

All breast cancers TAM NR 142 62 96

PLA NR 195 74 113

NR RR, 0.73 (0.58 to 0.91) RR, 0.84 (0.60 to 1.17) HR, 0.84 (0.64 to 1.10)

InvasiveAll

TAM 145 124 53 82

PLA 250 168 66 104

RR, 0.57 (0.46 to 0.70) RR, 0.74 (0.58 to 0.94) RR, 0.80 (0.56 to 1.15) HR, 0.78 (0.58 to 1.04)

ER+ TAM 70 87 40 53

PLA 182 132 52 86


ER- TAM 56 35 21 24

PLA 42 35 19 17


NoninvasiveAll

TAM 60 NR 9 NR

PLA 93 NR 6 NR

RR, 0.63 (0.45 to 0.89) NR RR, 1.50 (0.53 to 4.20) NR

LCIS TAM NR NR NR NR

PLA NR NR NR NR

NR NR NR NR

DCIS TAM NR 17 NR 14

PLA NR 27 NR 9

NR RR, 0.63 (0.32 to 1.20) NR NR


Adverse Events/ Side Effects: Tamoxifen vs. placebo


NSABP-P1 IBIS-I ITALIAN ROYAL MARSDENFollow-up (years) 7 (mean 6.2) 10 (median 8.0) 13 (median, 11.2) 20 (median, 13.2)Death TAM 126 65 36 54

PLA 114 55 38 54

RR, 1.10 (0.85 to 1.43) RR, 1.18 (0.81 to 1.73) HR, 0.96 (0.61 to 1.52) HR, 0.99 (0.68 to 1.44)

VTE All TAM NR 117 44 8c

PLA NR 68 28 3c

NR RR, 1.72 (1.27 to 2.36) RR, 1.63 (1.02 to 2.62) NR

DVT TAM 49 68 NR NR

PLA 34 37 NR NR

RR, 1.44 (0.91 to 2.30) RR, 1.84 (1.21 to 2.82)b NR NR

PE TAM 28 (see DVT) NR NR

PLA

13 NR NR

RR, 2.15 (1.08 to 4.51) NR NR

Cardiovascular TAM 113 NR NR 10c

PLA 109 NR NR 12c

RR, 1.03 (0.79 to 1.36) NR NR NR

Stroke TAM 71 15 6 7c

PLA 50 12 2 9c

RR, 1.42 (0.97 to 2.08) RR, 1.25 (0.55 to 2.93) RR, 3.11 (0.63 to 15.4) NR

TIA TAM 31 17 6 NR

PLA 34 22 5 NR

RR, 0.91 (0.54 to 1.52) RR, 0.77 (0.39 to 1.52) RR, 1.24 (0.38 to 4.08) NR


Adverse Events/Side Effects:Tamoxifen vs. placebo

*Sample size included in analyses; aShen et al, JNCI, 2008; bDVT and PE combinedAbbreviations: NSABP-P1, National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial P1; IBIS-I, International Breast Intervention Study; Italian, Italian Randomized Tamoxifen Prevention Trial; Royal Marsden, Royal Marsden Tamoxifen Trial; TAM, tamoxifen; PLA, placebo; NR, not reported in published literature; NA, not applicable; LCIS, lobular carcinoma in situ; AH, atypical hyperplasia; DCIS, ductal carcinoma in situ; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; TIA, transient ischemic attack; (xx to xx), 95% confidence interval.


NSABP-P1 IBIS-I ITALIAN ROYAL MARSDENFollow-up (years) 7 (mean 6.2) 10 (median 8.0) 13 (median, 11.2) 20 (median, 13.2)Endometrial Cancer

TAM 53 17 NR 13c

PLA 17 11 NR 5c

RR, 3.28 (1.87 to 6.03) RR, 1.55 (0.68 to 3.65) NR NR

Fracture TAM 116 240 NR 19c

PLA 80 235 NR 22c

RR, 0.68 (0.51 to 0.92) RR, 1.02 (0.86 to 1.21) NR NR

Cataract TAM NR 67 NR NR

PLA NR 54 NR NR

RR, 1.21 (1.10 to 1.34) RR, 1.24 (0.87 to 1.77) NR NR


Recommendations: Raloxifene•Should be discussed as an option to reduce the risk of invasive BC, specifically estrogen (ER)-positive breast cancer, in postmenopausal women who are ≥ 35 years of age with a 5-year projected absolute BC risk ≥ 1.66%,a or with LCIS.•May be used longer than 5 years in women with osteoporosis, in whom BC risk reduction is a secondary benefit.•Should not be used for BC risk reduction in premenopausal women.



Recommendations: Raloxifene•Is not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack, or during prolonged immobilization. •Discussions with patients and health care providers should include both the risks and benefits of raloxifene in the preventive setting.•DOSAGE: 60 mg/d orally for 5 years.



Results from Other SERM Trials



Results from Other SERM Trials CORE MORE RUTH STAR PEARL GENERATIONS

Follow-up (years)

4 + time inMORE trial

(median, 7.9)

4(median, 3.4)

7(median, 5.6)

8(median, 6.75)

5(median, 4.96)

4(median, NR)

BREAST CANCER INCIDENCENoninvasive

All

RAL: 16PLA: 7 HR, 1.12 (0.46 to 2.73)

RAL: NRPLA: NRNR

RAL: NR PLA: NRNR

RAL: 137TAM: 111RR, 1.22 (0.95 to 1.59)

LAS (.25mg): NRLAS (.5mg): NRPLA: NR

ARZ: NRPLA: NRNR

LCIS

RAL: NRPLA: NRNR

RAL:NR PLA: NRNR

RAL: NRPLA: NRNR

RAL: 34TAM: 33RR, 1.02 (0.61 to 1.70)

LAS (.25mg): NRLAS (.5mg): NR PLA: NR

ARZ: NRPLA: NRNR

DCIS

RAL: NRPLA: NRNR

RAL: NR PLA: NRNR

RAL: NRPLA: NRNR

RAL: 86TAM: 70RR, 1.22 (0.88 to 1.69)

LAS (.25mg): 4 HR, 1.00 (0.25 to 3.99)LAS (.5mg): 2HR, 0.50 (0.09 to 2.73)PLA: 4

ARZ: NRPLA: NRNR



Adverse Events/Side Effects:Other SERM Trials

CORE MORE RUTH STAR PEARL GENERATIONSADVERSE EVENTS/SIDE EFFECTSDeath

RAL: 47PLA: 29P=.27

RAL: NRPLA: NRHR, 0.61 (0.36 to 1.03)

RAL: 554PLA: 595 HR, 0.92 (0.82 to 1.03)

RAL: 202TAM: 236RR, 0.84 (0.70 to 1.02)

LAS (.25mg): 90HR, 1.38 (1.00 to 1.89)LAS (.5mg): 73HR, 1.12 (0.80 to 1.56)PLA: 65

ARZ: 105PLA: 98P=.62

VTE All

RAL: 47PLA: 13P=.094

RAL: NRPLA: NRNR

RAL: 103PLA: 71HR, 1.44 (1.06 to 1.95)

RAL: 154TAM: 202RR, 0.75 (0.60 to 0.93)

LAS (.25mg): 48HR, 2.67 (1.55 to 4.58)LAS (.5mg): 37HR, 2.06 (1.17 to 3.61)PLA: 18

ARZ: 63PLA: 27P<.001

DVT

RAL: 31PLA: 10P=.32

RAL: NRPLA: NRP=.002

RAL: 65PLA: 47HR, 1.37 (0.94 to 1.99)

RAL: 86TAM: 118RR, 0.72 (0.54 to 0.95)

LAS (.25mg): NRLAS (.5mg): NRPLA: NRNR

ARZ: 26PLA: 9P=.004

PE

RAL: 17PLA: 2P=.05

RAL: NRPLA: NRHR, 3.97 (0.91 to 17.3)

RAL: 36PLA: 24HR, 1.49 (0.89 to 2.49)

RAL: 68 TAM: 84RR, .080 (0.57 to 1.11)

LAS (.25mg): 12HR, 5.98 (1.34 to 26.7)LAS (.5mg): 9HR, 4.49; 0.97 to 20.8PLA: 2

ARZ: 16PLA: 7P=.06

Endometrial Cancer

RAL: 7PLA: 4P=.75

RAL: NRPLA: NRHR, 0.69 (0.22 to 2.18)

RAL: 21PLA: 27P=.53

RAL: 37TAM: 65RR, 0.55 (0.36 to 0.83)

LAS (.25mg): 3LAS (.5mg): 2PLA: 3NR

ARZ: 9PLA: 4P=.16




CORE MORE RUTH STAR PEARL GENERATIONSADVERSE EVENTS/SIDE EFFECTS

Cardiovascular

RAL: NRPLA: NRNR

RAL: NRPLA: NRNR

RAL: NRPLA: NRNR

RAL: 126TAM: 114RR, 1.10 (0.85 to 1.43)


ARZ: 116PLA: 113P=.88

Stroke

RAL: NRPLA: NRNR

RAL: NRPLA: NRHR, 0.68 (0.43 to 1.07)

RAL: NR PLA: NRHR, 1.10 (0.92 to 1.32)

RAL: 51TAM: 53RR, 0.96 (0.64 to 1.43)


ARZ: 47PLA: 42P=.59

TIA

RAL: NR PLA: NRNR

RAL: NRPLA: NRNR

RAL: NR PLA: NRNR

RAL: 50TAM: 41RR, 1.21 (0.79 to 1.88)

LAS (.25mg): 19HR, 1.35 (0.68 to 2.69)LAS (.5mg): 14HR, 1.00 (0.48 to 2.09)PLA:14

ARZ: NRPLA: NRNR




CORE MORE RUTH STAR PEARL GENERATIONSADVERSE EVENTS/SIDE EFFECTSFracture

RAL: NRPLA: NR P<.05

RAL: 64PLA: 97 RR, 0.66 (0.55 to 0.81)

RAL: V 64; NV 428PLA: V 97; NV 438 V: HR, 0.65 (0.47 to 0.89); NV: HR, 0.96 (0.84 to 1.10)

RAL: 96TAM: 104 RR, 0.92 (0.69 to 1.22)

LAS (.25mg): V: 189/2734HR, 0.69 (0.57 to 0.83)NV: 269/2852 HR, 0.90 (0.76 to 1.06)LAS (.5mg): V: 156/2748HR, 0.58 (0.47 to 0.70)NV: 230/2852HR, 0.76 (0.64 to 0.91)PLA: V: 262/2744 (HR, NR)NV: 296/2852 (HR, NR)

ARZ: V: 109/4192NV: 334/4192PLA: V: 179/4162NV: 354/4162 V: RR, 0.61 (0.48 to 0.77); NV: RR, 0.94 (0.81 to 1.10)

Cataract

RAL: NRPLA: NRNR

RAL: NRPLA: NRNR

RAL: 374PLA: 391P=.56

RAL: 603TAM: 739RR, 0.80 (0.72 to 0.89)

LAS (.25mg): NRLAS (.5mg): NRPLA: NRNR

ARZ: NR PLA: NRNR

Abbreviations: TAM, tamoxifen; RAL, raloxifene; PLA, placebo; LAS, lasofoxifene; ARZ, arzoxifene; NR, not reported in published literature; V, vertebral fractures; NV, nonvertebral fractures; (xx to xx), 95% confidence interval; CORE, Continuing Outcomes Relevant to Evista; MORE, Multiple Outcomes of Raloxifene Evaluation; RUTH, Raloxifene Use for the Heart; STAR, National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial P2; PEARL, Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene; GENERATIONS, Generations Trial; LCIS, lobular carcinoma in situ; AH, atypical hyperplasia; DCIS, ductal carcinoma in situ; DVT, deep vein thrombosis; PE, pulmonary embolism; TIA, transient ischemic attack.



Recommendations: Exemestane•Should be discussed as an alternative to tamoxifen and/or raloxifene to reduce the risk of invasive breast cancer, specifically estrogen (ER)-positive breast cancer, in postmenopausal women who are ≥ 35 years of age with a 5-year projected absolute BC risk ≥ 1.66%, or with LCIS or atypical hyperplasia.•Should not be used for BC risk reduction in premenopausal women.•Discussions with patients and health care providers should include both the risks and benefits of exemestane in the preventive setting.•DOSAGE: 25 mg/d orally for 5 years.



Results from Aromatase Inhibitor Trials: MAP.3Follow-up (years) 3 (median): range 0 to 63.4 monthsBREAST CANCER INCIDENCESample size* EXE:2285, PLA:2275

All breast cancersEXE: 20PLA: 44HR, 0.47 (0.27 to 0.79 )

InvasiveAll

EXE: 11, PLA: 32HR, 0.35 (0.18 to 0.70)

ER+

EXE: 7PLA: 27HR, 0.27 (0.12 to 0.60)

ER-

EXE: 4PLA: 5HR, 0.80 (0.21 to 2.98)

Noninvasive All NR

LCIS

EXE: 4PLA: 11HR, 0.36 (0.11 to 1.12)b

DCIS

EXE: 9PLA: 14HR, 0.65 (0.28 to 1.51)



Results from Aromatase Inhibitor Trials: MAP.3

Follow-up (years) 3 (median): range 0 to 63.4 monthsADVERSE EVENTS/SIDE EFFECTSSample Size EXE: 2240

PLA: 2248

Death

EXE: 19PLA: 19NR

VTE All

EXE: 11PLA: 7NR

DVT NRPE NR

Cardiovascular

EXE: 106PLA: 111P=.78

Stroke

EXE: 13PLA: 11NR

TIA (see stroke)Endometrial Cancer

EXE: 5PLA: 8NR

Fracture

EXE: 149PLA: 143P=.72

Cataract NR

*Sample size included in analyses; aOnly results from cognitive subprotocol available (Jenkins et al, Lancet Oncol, 2008). Abbreviations: EXE, exemestane; ANA, anastrozole; PLA, placebo; NR, not reported in published literature; IBIS-II, International Breast Intervention Study (II) ; LCIS, lobular carcinoma in situ; AH, atypical hyperplasia; DCIS, ductal carcinoma in situ; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; TIA, transient ischemic attack.bResults for incidence of atypical ductal hyperplasia, atypical lobular hyperplasia, and LCIS combined



Patient and Clinician CommunicationKey Discussion Points

•Assessment and discussion of individual risk of developing breast cancer

•Options for reducing the risk of developing breast cancer (non-pharmacologic and pharmacologic)

•Potential impact of specific chemoprevention agents on the incidence of both invasive and noninvasive breast cancers

•Potential risks and side effects of chemoprevention agents



Patient and Clinician CommunicationKey Discussion Points

•Long-term effectiveness of the chemoprevention agents

•Chemoprevention studies were not powered to detect differences in mortality as it was considered that a reduction in incidence was itself an important clinical endpoint.

•Accessibility - cost/insurance coverage

•Resources/materials for consideration (e.g. www.cancer.net)

•Plan for follow-up.



Health Disparities•Challenges to minimizing health disparities include:

• Equal access to health care

• Racially diverse participation in clinical trials

• Improved risk assessment models

•Racial, ethnic, and socioeconomic status may affect health outcomes and/or create barriers to access and use of chemoprevention agents for BCRR

• In addition to age and comorbidities, race is important when considering risk-benefit profiles, so race-specific estimates should be considered and incorporated in discussions between patients and clinicians



Future Directions•Need for:

• Research to address poor uptake of BCRR in high-risk women

• Effective tools and approaches to educate providers on chemoprevention

• Efficacious interventions that communicate to eligible women the risks and benefits of specific chemoprevention agents

• Tools that more accurately identify women at increased risk

• Greater understanding of what disparities and barriers exist with regard to chemoprevention use among high-risk women



The Bottom Line•Intervention

• Pharmacologic interventions for breast cancer risk reduction, including selective estrogen receptor modulators and aromatase inhibitors

•Target Audience• Medical Oncologists, Surgical Oncologists, Gynecologists, Primary Care

Physicians, General Practitioners

•Key Recommendations • Tamoxifen (20 mg/d orally for 5 years) should be discussed as an option to

reduce the risk of invasive breast cancer, specifically estrogen (ER)-positive breast cancer, in premenopausal or postmenopausal women ≥ 35 years of age at increased risk of breast cancer, or with lobular carcinoma in situ (LCIS). Tamoxifen is not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, during prolonged immobilization, in women who are pregnant or who may become pregnant, or nursing mothers. Tamoxifen is not recommended in combination with hormone therapy.



The Bottom Line•Key Recommendations

• Raloxifene (60 mg/d orally for 5 years) should be discussed as an option to reduce the risk of invasive breast cancer, specifically ER-positive breast cancer, in postmenopausal women ≥ 35 years of age at increased risk of breast cancer, or with LCIS. It should not be used for breast cancer risk reduction in premenopausal women. Raloxifene is not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization.

• Exemestane (25 mg/d orally for 5 years) should be discussed as an alternative to tamoxifen or raloxifene to reduce the risk of invasive breast cancer, specifically ER-positive breast cancer, in postmenopausal women ≥ 35 years of age at increased risk of breast cancer, or with LCIS or atypical hyperplasia. Exemestane should not be used for breast cancer risk reduction in premenopausal women.

• For tamoxifen and raloxifene, the most favorable risk-benefit profile is seen in women at greatest risk of developing breast cancer.



The Bottom Line•Key Recommendations (con’t)

• Discussions with patients and health care providers should include both the risks and benefits of each agent under consideration.

• NOTE1: Refer to Table 1 for the complete recommendations.• NOTE2: Increased risk is defined as a 5 year projected absolute risk of breast

cancer ≥1.66% on the NCI Breast Cancer Risk Assessment Tool or an equivalent measure.

• NOTE3: Trials were not designed to assess mortality and the impact of the agent on overall survival or breast cancer-specific survival has not been demonstrated in 10 years of follow-up.

•Methods• A systematic review of randomized controlled trials and meta-analyses

published from June 2007 through June 2012 was completed using MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed the evidence to determine whether the 2009 ASCO clinical practice guideline recommendations needed to be updated.



Additional Resources•A Data Supplement and clinical tools and resources can be found on ASCO’s Web site at:

• http://www.asco.org/guidelines/bcrr

•Patient information is also available at:

• http://www.asco.org/guidelines/bcrr

• http://www.cancer.net/publications-and-resources/what-know-ascos-guidelines/what-know-ascos-guideline-drugs-lower-breast-cancer-risk

• www.cancer.net/bcriskinfo


http://www.asco.org/guidelines/bcrr





Update Committee Panel MembersUPDATE COMMITTEE MEMBER AFFILIATION

Kala Visvanathan, MD, MHS, Co-Chair

Johns Hopkins Medical Institutions, Baltimore, MD

Scott M. Lippman, MD, Co-Chair

Moores Cancer Center, University of California, San Diego, CA

Elissa Bantug, MHS Johns Hopkins Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD

Powel Brown, MD, PhD MD Anderson Cancer Center, University of Texas, Houston, TX

Nananda Col, MD, MPH University of New England, Biddeford, ME

Jack Cuzick, PhD Queen Mary University of London, UK

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute and UPMC CancerCenter, Pittsburgh, PA

Andrea De Censi, MD E.O. Ospedali Galliera, Italy

Carol Fabian, MD University of Kansas Medical Center, Kansas City, KS


Update Committee Panel MembersUPDATE COMMITTEE MEMBER AFFILIATION

Leslie Ford, MD National Cancer Institute, Bethesda, MD

Judy Garber, MD, MPH Dana Farber Cancer Institute, Boston, MA

Maria Katapodi, PhD, RN, FAAN University of Michigan School of Nursing, Ann Arbor, MI

Barnett Kramer, MD, MPH National Cancer Institute, Bethesda, MD

Monica Morrow, MD Memorial Sloan Kettering Cancer Center, New York, NY

Barbara Parker, MD Moores Cancer Center, University of California, San Diego, CA

Carolyn Runowicz, MD Herbert Wertheim College of Medicine, Florida International University, Miami, FL

Victor Vogel III, MD Geisinger Medical Center Cancer Institute, Danville, PA

James L. Wade, MD Cancer Care Specialists of Central Illinois, Decatur, IL


ASCO GuidelinesThe clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action.


ASCO Guidelines[Cont’d] The use of words like “must,” “must not,” “should,” and “should not” indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an “as is” basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.


BREAST CANCER RISK REDUCTION Clinical Practice Guideline Update © American Society of Clinical Oncology®.

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