Kevin S. Hughes, MD, FACS Co-Director, Avon Comprehensive Breast Evaluation Center Massachusetts General Hospital Surgeon The Newton-Wellesley Hospital Breast Center Risk Assessment and Individualized Screening

Under the HIPAA Privacy Rule, may a health care provider disclose protected health information about an individual to another provider, when such information is requested for the treatment of a family member of the individual? Yes. Thus, the Rule does permit a doctor to disclose protected health information about a patient to another health care provider for the purpose of treating another patient (e.g., to assist the other health care provider with treating a family member of the doctor’s patient). 1/12/2009

For example, an individual’s doctor can provide information to the doctor of the individual’s family member about the individual’s adverse reactions to anesthetics prior to the family member undergoing surgery. These uses and disclosures are permitted without the individual’s written authorization or other agreement

RT Risk After Hodgkins Age of RTRR of breast cancer < to Cancer 79:1203, 1997

Breast Density 15,292 women presenting for mammography at the MGH Avon Breast Center

75% of time can predict density if you know age and BMI Density without information about age and BMI is meaningless No model uses age, height and weight in determining level of risk

Breast cancer RRRR Family history BRCA1-2 Early menarche LateFLB BreastBx Modified from New England Journal of Medicine 1992;327: RTinteens AHLCIS

Saslow D et. al. CA Cancer J Clin 2007; 57: 75

ACS MRI Guidelines Saslow D et. al. CA Cancer J Clin 2007; 57: 75

ACS MRI Guidelines Exclude Gail Model …less useful than BRCAPro, Claus, and Tyrer-Cuzick …not adequate for evaluating family history Therefore we do not recommend its use for evaluating patients for breast MRI screening Online Supplemental Material

ACS Guidelines Claus Breast FH BRCAPRO Breast and ovarian FH Tyrer-Cuzick Breast and ovarian FH Pathologic factors Hormonal factors

10,000 4/1/2006 to 9/17/2007 7,821 NULL or No Never HORMONES 6,981 W/ Gail Score 6,028 W/ BRCAPRO Lifetime 5,894 W/ BRCAPRO Mutation and Tyrer-Cuzick LCIS/AH status not available

Tyrer-Cuzick = 44BRCAPRO = Overlap of BRCA 1 or 2 Mutation Risk 10% or greater

Tyrer-Cuzick= 330 (5.6%) 276 BRCAPRO = 25 (0.4%) Claus = 54 (0.9%) Lifetime Breast Cancer Risk 20% or greater by Model

20% or greater LT Risk

Breast cancer RRRR Family history BRCA1-2 Early menarche LateFLB BreastBx Modified from New England Journal of Medicine 1992;327: RTinteens AHLCIS

Options for high risk

Prophylactic Oophorectomy Screening Chemoprevention Options for high risk

IDing patients for MRI is not enough Need complete risk assessment Genetic testing as appropriate Manage Breast and Ovarian Risk! Consider Genetic Testing if Risk Mutation is 10% or greater

Mutation Risk Greater than or equal to 10% Cost benefit –Test 10 people at $3500 each –Willing to pay $35,000 to find 1 carrier

Avon Comprehensive Breast Center Database 18,190 screening mammogram patients 40 or older –(May 2003 – July 2005) –BRCAPRO run on all

Avon Comprehensive Breast Center Database Lifetime risk ≥20% 78 (0.4%) Predicted Mutation Carriers 27 BRCAPRO 18,190 screening mammogram patients 40 or older –(May 2003 – July 2005) –BRCAPRO run on all

Avon Comprehensive Breast Center Database 374 (2.1%) Predicted Mutation Carriers 62 BRCAPRO Mutation Risk ≥10% Lifetime Risk <20% and 18,190 screening mammogram patients 40 or older –(May 2003 – July 2005) –BRCAPRO run on all

MGH Screening Data: All Comers Risk of Mutation Risk of Breast Cancer n Mean Probability of Mutation Projected # Mutation Carriers ≥10%≥20% ≥10%<20%

Suggested Strategy ≥10% risk of mutation –Genetic testing Positive-Manage with all modalities Negative-Your call –Based on FH

ACS MRI Guidelines Saslow D et. al. CA Cancer J Clin 2007; 57: 75 LCIS/AH

20% or greater lifetime risk –Any LCIS age 69 and below –Any AH age 56 and below Tyrer Cuzick for AH & LCIS Even more with even trivial risk factors

Breast cancer RRRR Family history BRCA1-2 Early menarche LateFLB BreastBx Modified from New England Journal of Medicine 1992;327: RTinteens AHLCIS

Radiation to chest age 30 or less

Breast cancer RRRR Family history BRCA1-2 Early menarche LateFLB BreastBx Modified from New England Journal of Medicine 1992;327: RTinteens AHLCIS

Gail >1.66% at 5 years Maybe Raloxifene if osteopenia/porosis ?

Breast cancer RRRR Family history BRCA1-2 Early menarche LateFLB BreastBx Modified from New England Journal of Medicine 1992;327: RTinteens AHLCIS

Clarifying the Risk of Breast Cancer in Women with Atypical Breast Lesions SB Coopey, E Mazzola, JM Buckley, J Sharko, AK Belli, EMH Kim, F Polufriaginof, G Parmigiani, JE Garber, BL Smith, MA Gadd, MC Specht, AJ Guidi, CA Roche, KS Hughes Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA; Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Department of Medical Oncology, Dana- Farber Cancer Institute, Boston, MA; Department of Pathology, Newton-Wellesley Hospital, Newton, MA San Antonio Breast Cancer Symposium—December 6-10, 2011

Methods All electronically available pathology –Mass General, Brigham & Women’s, Newton Wellesley Natural Language Processing (Clearforest, Waltham, MA) –Atypia diagnoses verified by human reader All women diagnosed with ADH, ALH, LCIS, or Severe ADH –No prior or concurrent breast cancer –Intact breasts Trumping order for maximum diagnosis –Severe ADH> LCIS > ALH > ADH Use of chemoprevention agents identified by chart review –Yes, No, Unknown Effect of chemoprevention analyzed from 1999 forward This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011

Natural Language Processing of breast pathology reports DiagnosisPhrases Invasive Ductal Carcinoma124 Invasive Lobular Carcinoma95 Ductal Carcinoma in situ52 Lobular Carcinoma in situ53 Atypical Lobular Hyperplasia17 Atypical Ductal Hyperplasia14

Natural Language Processing of breast pathology reports DiagnosisPhrasesNegateTotal Patterns Invasive Ductal Carcinoma Invasive Lobular Carcinoma Ductal Carcinoma in situ Lobular Carcinoma in situ Atypical Lobular Hyperplasia Atypical Ductal Hyperplasia negations before diagnosis ( No evidence of …) 12 negations after diagnosis ( … was not seen)

Results 76,333 breast pathology reports –42, 950 individuals 2942 women with atypia –Mean Age Dx: 53 years (range: 19-93) –Mean FU all: 66 months This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011

Breast Cancer Risk by Atypia Type No Chemoprevention (All years) This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011 Time from Atypia to Cancer (years) Probability of Being Cancer Free 5-Year10-Year ADH 4.5%17.3% ALH 10.9%20.7% LCIS 10.5%23.7% Severe ADH 9.7%26% *ADH at 5 years only significant difference

Results: Chemoprevention Status Limited to 1999 and beyond, n= (18.9%) patients treated –Tamoxifen, raloxifene, and/or exemestane –Any duration of time 1472 (59.8%) patients not treated 522 (21.2%) patients with data unavailable This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011

Probability of Cancer after Atypia Diagnosis With and Without Chemoprevention, 1999 and Beyond This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011 Chemoprevention Yes (n=466) No (n=1472) Probability of Being Cancer Free Time from Atypia to Cancer (years) (p<0.05) 8.3% 21.3% 4.1% 7.5%

Chemoprevention Decreased Cancer Risk for all Atypia Types 1999 and Beyond ADH San Antonio Breast Cancer Symposium—December 6-10, 2011 Borderline LCIS ALH 8.5% 19.9% 14.7% 2.1% 10.3% 32.4% 8.5% 18.7% (p<0.05)

Atypical hyperplasia/LCIS Chemoprevention!

Risk Categories Highest risk –BRCA1/2 carrier –Radiation to chest age 30 or less High Risk –Atypical hyperplasia/LCIS Elevated risk –Gail >1.66% at 5 years Prophylactic surgery MRI Chemoprevention ?Chemoprevention

Laterality of Cancer with No Chemoprevention Number of Cancers Ipsilateral Cancer Contralateral Cancer Bilateral Cancer Side Unknown Severe ADH (n=21) 47.6%42.8% 4.8% LCIS (n=45) 55.6%37.8% 4.4%2.2% ADH (n=57) 59.6%38.6% 1.8%0% ALH (n=61) 60.7%37.7% 0%1.6% This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011 Significantly more ipsilateral cancers for all atypia types combined (p<0.005)

Invasive/DCIS with No Chemoprevention Number of Cancers Invasive Cancer Non-Invasive Cancer ADH (n=57) 47.4%52.6% Severe ADH (n=21) 57.1%42.9% ALH (n=61) 68.9%31.1% LCIS (n=45) 71.1%28.9% This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011 invasive vs non-invasive cancer ADH and Borderline: No significant difference ALH and LCIS: p<0.001

Conclusions ADH, ALH, LCIS, and Borderline DCIS increase a woman’s risk of breast cancer to a similar amount Chemoprevention for all atypia types significantly reduces breast cancer risk at 5 and 10 years Increased use of chemoprevention for patients with atypia will significantly decrease cancer risk This data will be used to create a better model of breast cancer risk prediction based on atypia type and efficacy of chemoprevention This presentation is the intellectual property of the author/presenter. Contact at for permission to reprint and/or San Antonio Breast Cancer Symposium—December 6-10, 2011

Current EHR Future EHR Mostly free text Structured data Using free text for CDS will require Natural Language Processing and is not trivial

Natural Language Processing of breast pathology reports DiagnosisPhrases Invasive Ductal Carcinoma124 Invasive Lobular Carcinoma95 Ductal Carcinoma in situ52 Lobular Carcinoma in situ53 Atypical Lobular Hyperplasia17 Atypical Ductal Hyperplasia14

Natural Language Processing of breast pathology reports DiagnosisPhrasesNegateTotal Patterns Invasive Ductal Carcinoma Invasive Lobular Carcinoma Ductal Carcinoma in situ Lobular Carcinoma in situ Atypical Lobular Hyperplasia Atypical Ductal Hyperplasia negations before diagnosis ( No evidence of …) 12 negations after diagnosis ( … was not seen)

Our Goal Find every mutation carrier for every hereditary syndrome known to man before disease occurs

BRCA1/2 Mutation carriers in the US ~1,000,000 carriers nCarriers Jewish (1/40) 6,191,281154,782 Not Jewish (1/350) 275,230,624786, ,421, ,155

BRCA1/2 Mutation carriers in the US Females 20 and above Close to 350,000 carriers 20 and older nCarriers Jewish (1/40) 229,108657,277 Not Jewish (1/350) 101,849,202290, ,274

15 years of genetic testing BRCA tests to date – ~ 500,000 Assume 10% positive – 50,000 BRCA1/2 carriers found Assume most tested patients had cancer –95 to 99% of unaffected carriers not tested Likely the best of any adult hereditary syndrome

Options for high risk

Prophylactic Oophorectomy Screening Chemoprevention Options for high risk

Family history Multiple relatives affected Young age at diagnosis Multiple primary cancers Unusual Cancer Male breast cancer

To identify high risk Eyeball pedigree Guidelines Risk models

NCCN Practice Guidelines (2005) 1. Member of a family with a known BRCA1/BRCA2 mutation 2. Personal history of breast cancer plus one or more of the following: a) Diagnosed 40 years, with or without family history b) Diagnosed 50 years, or bilateral, with at least one close blood relative with breast cancer diagnosed 50 years or at least one close blood relative with ovarian cancer c) Diagnosed at any age, with at least two close blood relatives with ovarian cancer at any age d) Diagnosed at any age with breast cancer with at least two close* blood relatives with breast cancer, especially if at least one is diagnosed before age 50 years or has bilateral disease e) Close male blood relative has breast cancer f) Personal history of ovarian cancer g) Is of ethnic descent associated with deleterious mutations (e.g., Ashkenazi Jewish) 3. Personal history of ovarian cancer plus one or more of the following: a) At least one close* blood relative with ovarian cancer b) At least one close* female blood relative with breast cancer at age 50 years or bilateral breast cancer c) At least two close* blood relatives with breast cancer d) At least one close* male blood relative with breast cancer e) Is of Ashkenazi Jewish descent 4. Personal history of male breast cancer plus one or more of the following: a) At least one close male blood relative with breast cancer b) At least one close female blood relative with breast or ovarian cancer c) Ashkenazi Jewish descent 5. Family history only: close family member (on the same side of the family) meeting any of the above criteria 2. Personal history of breast cancer plus one or more of the following: a) Diagnosed under 40 years, with or without family history b) Diagnosed under 50 years, or bilateral, with at least one close blood relative with breast cancer diagnosed under 50 years or at least one close blood relative with ovarian cancer c) Diagnosed at any age, with at least two close blood relatives with ovarian cancer at any age d) Diagnosed at any age with breast cancer with at least two close* blood relatives with breast cancer, especially if at least one is diagnosed before age 50 years or has bilateral disease e) Close male blood relative has breast cancer f) Personal history of ovarian cancer g) Is of ethnic descent associated with deleterious mutations (e.g., Ashkenazi Jewish)

Risk Models Risk of mutationLifetime risk BRCAPRO Tyrer-Cuzick Myriad BRCAPRO Tyrer-Cuzick Claus Gail

Dependant on paper form plus memory

Currently: Paper + memory Patient completes paper form Reviews data using memory of guidelines Orders Genetic Testing

EHR: Paper + extra work + memory Patient completes paper form Reviews data using memory of guidelines Orders Genetic Testing Staff enters data into the EHR

Clinical Decision Support (CDS) Apply Algorithms/Guidelines to patient data Identify best course of action Results displayed as intuitive Visualizations BRCAPRO Mutation Risk 25% Suggest Genetic Testing Facilitates best action as part of workflow

HughesRiskApps.com Patient enters data into Tablet PC or iPad Reviews Report & Pedigree Reviews suggested management Orders Genetic Testing Patient educational materials Clinical Decision Support

Newton Wellesley Hospital Since 4/ unique patients 2255 (4.5%) mutation risk 10% or greater

Women at elevated risk and their PCP are sent a letter

Highest risk –BRCA1/2 carrier –Radiation to chest age 30 or less High Risk –Atypical hyperplasia/LCIS Elevated risk –Gail >1.66% at 5 years Prophylactic surgery MRI Chemoprevention ?Chemoprevention Conclusions

Risk Categories Highest risk –BRCA1/2 carrier –Radiation to chest age 30 or less High Risk –Atypical hyperplasia/LCIS Elevated risk –Gail >1.66% at 5 years Prophylactic surgery MRI Chemoprevention ?Chemoprevention

Family history & selective testing Population based genetic testing Find all mutation carriers Adult syndromes Newborn screening

Tumor suppressor gene Product of the gene helps prevent the development of cancer

Normal Breast Cell Chromosome 17 Normal BRCA1 Functioning Protein

Breast Cell with BRCA1 Mutation Chromosome 17 Normal BRCA1 Chromosome 17 Mutated BRCA1 Non- functioning Protein Functioning Protein

Normal Gene Lost Cancer Not Prevented Chromosome 17 Normal BRCA1 Lost Chromosome 17 Mutated BRCA1 Non- functioning Protein

Hereditary vs Sporadic Cancer Knudson’s 2 hit hypothesis HEREDITARY CANCER SPORADIC CANCER

20 to 25% LT Risk of…What? Invasive cancer –BRCAPRO Invasive plus DCIS –Claus –Tyrer-Cuzick

Options for high risk

Conclusions ≥10% risk of mutation –Genetic testing Positive-Manage with all modalities Negative-Your call –Depend on FH ≥20% LT Risk –Lots by TC –Almost all LCIS and AH by TC –Do they all need MRI?

Better Strategy Identify mutation carriers (genetic testing) –Offer ALL risk reducing strategies Oophorectomy Prophylactic mastectomy MRI Mammography ? Chemoprevention

Tyrer-Cuzick= 330 (5.6%) 263 Claus = 54 (0.9%) Lifetime Breast Cancer Risk 20% or greater by Model Adjusted BRCAPRO 61 (1%)

ACS Guidelines Saslow D et. al. CA Cancer J Clin 2007; 57: 75 BRCAPRO Tyrer-Cuzick Claus Gail