NeoMatrix

Introduction to Risk Assessment

using NAF and HALO

Facts about Breast Cancer

• 8 of 9 women who develop breast cancer have no primary family history

• 70% of the women in the US who develop breast cancer have no known identifiable risk factors other than age

• The most common cause of death for women 35-50 is breast cancer• Mammograms are indicated for women > 40 years old*

– Less effective for detecting BC in younger women

– Many breast cancers grow slowly, taking an average of 8 years before they can be detected by mammography

– Compliance is variable

• The presence of atypical cells (“atypia”) in the breast impart a higher risk of developing BC, and can signal occult disease.– Non-invasive testing using Nipple Aspirate Fluid (NAF) cytology is a

studied, proven method for detecting the presence of atypia

•US Preventive Services Task Force now recommends screening at age 50> , Ann Intern Med. 2009 Nov 17;151(10):727-37, W237-42

Cervical Pap Tests have dramatically reduced mortality Progress against Breast Cancer has been modest

Source: American Cancer Society, Surveillance Research 2006

Unmet Clinical

Need

Pap Intro

Cervical

Breast

1943: Cytologic cervical pap test introduced

1958: Dr. George Papanicolaou finds that NAF cytology is valuable in diagnosing breast disease.

1960: Mammography introduced for breast cancer screening.

2007: HALO Breast Pap Test provides opportunity to use cytologic evaluation of NAF to differentiate between normal and pre-malignant cells

Biology of “Atypia”

Cellular and/or Histologic Atypia: a reflection of MUTATIONS – genomic in all cells; somatic (environmental) in scattered cells – that impart a growth advantage

These mutations are the common denominator of ALL risk factors – known & unknown. The historical “field effect” (once used to support mastectomy) is actually a valid concept at the molecular level -- the “field” is BOTH breasts.

(simplified, conceptual framework for ER+ carcinogenesis)

Slide credit: Dr. Alan Hollingsworth, Mercy Women’s Center and Mercy Cancer Center at Mercy Health Center in Oklahoma City

ADH, ALH/LCIS predict risk to ADH, ALH/LCIS predict risk to all breast tissueall breast tissue, , independent of where an abnormality is discoveredindependent of where an abnormality is discovered

Blue = normal

GreenGreen = hyperplasia

Red = Atypia

Biopsy uncovers ADH,

if it is within the sample

• ADH, ALH/LCIS are “non-obligated pre-malignant markers” that reflect underlying genetic/environmental insults

• And, there are no genetic or environmental risks that impact only one breast (field effect)

Slide credit: Dr. Alan Hollingsworth, Mercy Women’s Center and Mercy Cancer Center at Mercy Health Center in Oklahoma City

Photo credits: N.I.H.Histologic ADH – based mostly on architecture, while cytology is secondary, as long as cells are monomorphic, low or hi grade

Cytologic Atypia (a.k.a “hyperplasia with atypia”) - is based on many cytologic features, but also takes into account the relationship among cells (architecture)

Histologic Atypia vs Cytologic Atypia

Slide credit: Dr. Alan Hollingsworth, Mercy Women’s Center and Mercy Cancer Center at Mercy Health Center in Oklahoma City

Multiple studies demonstrate that either cytologic atypia or ADH confers 4-5x increased relative risk of BC

ADH or cytologic atypia —risk conferral is similar.

20,000 Patients in Multiple Studies 20+ Years Follow-Up Nearly 100 Peer Reviewed Publications NCI, ASBS, ACOG Recognize Importance of atypia

Supports the use of non-invasive NAF collection (HALO) as a

method to obtain additional,

valuable risk information on asymptomatic

patients

Risk Factors of Breast Cancer

Definition of Risk Factor Anything that affects a person's absolute risk of developing a disease is a risk factor.

•Gender (100% risk)•Age•Family history - Genetic Mutations (BRCA-1 and BRCA-2)•Endogenous (from within) hormones: Menarche, Childbirth/Nulliparity, Menopause•Exogenous (external) hormones: OCP, HRT•Tissue risk: hyperplasia and breast density•Breast Density•Radiation exposure•Lifestyle

Relative Risk for Selected Factors

Rating the Risk Factors for Breast Cancer, S. Eva Singletary, MD, FACS, Annals of Surgery--Ann Surg. 2003 Apr;237(4):474-82. Review.

Do you know your patient’s BC risk?

• Quantitative risk models launched in 1990’s with Breast Cancer Prevention trials– Gail model reviews primary family history and other factors (widely used)– Tyrer-Cuzick model extends Gail to multiple other known risk factors, including secondary family history and paternal

history

• NAF cytology confirms that women < 55 who test positive for NAF epithelial cells are over >4x more likely to develop breast cancer

Current Screening Methods: Standard of Care

• Clinical Breast Exam– Help detect BC in asymptomatic women, value for women who

don’t get regular mammograms

– Yield: 0.5%*

• Mammography (women > 40):– Even with aggressive screening strategies, most breast cancers

are still discovered in the invasive stages. – Yield: 1% for initial screen; 0.3-0.5% on annual screens

• MRI (ACS guideline: only high-risk patients after neg. mammos)– Yield: 2-3% for initial screen; 1% on annual screens– ACS has no policy “for or against” MRI screening for women

between 15-19% lifetime risk, including such risks as prior cancer, atypical hyperplasia, LCIS, dense breasts, or weaker family history

*Bobo JK, Lee NC, Thames SF. Findings from 752,081 clinical breast examinations reported to a national screening program from 1995 through 1998. J Natl Cancer Inst 2000Slide credit: Dr. Alan Hollingsworth, Mercy Women’s Center and Mercy Cancer Center at Mercy Health Center in Oklahoma City

Screening for Disease vs Comprehensive Risk Assessment

• Every time a family history is taken, you are screening for Risk Factors

• Analogous to blood testing for hyperlipidemia: – Not screening for current cardiac disease, rather a risk factor for

the development of cardiac disease– available interventions facilitate mortality reduction

• When you screen for “atypia” (with NAF), you are screening for risk factors – With all such identifiable risks, outcome-proven risk-reducing

strategies and high-risk surveillance are available interventions

Slide credit: Dr. Alan Hollingsworth, Mercy Women’s Center and Mercy Cancer Center at Mercy Health Center in Oklahoma City

Comprehensive Risk Assessment (RA)

• Risk Models (Gail, Tyrer-Cuzick, etc.)– When “cellular atypia” is plugged into either model, usually

results in “greater than 20%” for women < 50, and almost always for women < 40

• Important to KNOW presence of atypia• Most agree that cytologic and cellular atypia are equivalent for RA purposes

* Hollingsworth, et al. Current comprehensive assessment and management of women at increased risk for breast cancer. American Journal of Surgery—2004Slide credit: Dr. Alan Hollingsworth, Mercy Women’s Center and Mercy Cancer Center at Mercy Health Center in Oklahoma City

“Perhaps the most important concept in this area is that breast cancer risk is fluid. It changes with time. Therefore, breast cancer risk assessment should be repeated periodically to allow the patient the benefit of updated information, as well as the opportunity to change the risk management strategy she previously employed.”*

- Risk Assessment Working Group -

Comprehensive Risk Assessment (RA)

• NAF Cytology– Yield: 0.7-2.7% for atypia in a normal, asymptomatic population– Ductal Carcinoma in Situ (DCIS) may be present 5 or more years

prior to invasion, and atypical hyperplasia (AH – “atypia”) many years prior to that

Use of NAF cytology: an attempt to identify some of the 70% whose risk

factors (atypia) are present, but occult.

Slide credit: Dr. Alan Hollingsworth, Mercy Women’s Center and Mercy Cancer Center at Mercy Health Center in Oklahoma City

90-95% visible on X-ray

90-95% with X-ray & MRI

plus breast MRI

MRI

NAF cytology

Taking a bite out of submerged

pathology

NeoMatrix: HALO Breast Pap Test

• FDA cleared• Indicated for the collection of

NAF for cytological evaluation in the determination and/or differentiation of normal vs. pre-malignant cells

• Over 60,000 procedures performed to date

• Console has a small footprint (15”x13.5”x18”) and moves easily between rooms

How HALO can benefit your practice

• Disposables priced at a nominal cost, designed for single patient use

• Multiple options to own, lease, free-use program or rent console • Can be performed by a nurse or medical assistant• Labs processing NAF select an appropriate CPT code depending on

the method they will use to process the sample– This is typically reimbursed, subject to patient deductible

• In-office NAF collection currently is not reimbursed by 3rd party payers

• HALO trained labs are available to analyze specimens• Typical charge to patient is $75-150 (determined by practice)• HALO can add revenue to support this, and other, advancements in

patient

How HALO works

• Simple, test takes 5 minutes, easily fits into an annual wellness visit• Uses warmth and suction to obtain NAF• Well tolerated – over 80% of women would recommend to a friend and

have the test again• Sample processing uses liquid based cytology similar to that of cervical

pap

What do HALO results mean?

• Patient who does not yield fluid is at normal risk – her risk remains 1 in 8• Patient who produces fluid with cells but no atypia is at an above average

risk and should be closely monitored• Patient who produces atypia is at an elevated risk and should undergo

comprehensive risk assessment

Care Path for HALO patients

• ~50% of patients will not yield NAF– Continue annual screening

and other risk assessment methods

• ~50% will yield fluid and should follow the algorithm to right

Risk Reduction Strategies for Consideration

• Lifestyle changes– High fiber diet– Weight management– Exercise– Reduction of alcohol intake

• Chemoprevention with SERMs– Based on threshold numbers

• Preventive mastectomies with reconstruction – Based on patient desires after understanding probabilities and

overall risk profile including multiple risk factors– Mastectomy is rarely, if ever, indicated for a finding of atypia

alone

National Cancer Institute: http://www.cancer.gov/cancertopics/pdq/prevention/breast/healthprofessional

A negative NAF test does not rule out cancer any more than …

- Negative history for risk factors- A low number on the Gail model or other risk tool- A negative BRCA test- A negative self or clinical breast exam- A negative mammogram

A false sense of security exists with ALL of the above

Atypia is a known, elevated risk factor for breast cancer. Collection of NAF using HALO is the only non-invasive, automated method for collecting NAF and assessing this individual risk.

Clinical Validation for HALO

• Leverages work performed since the 1970’s on cytologic atypia as an increased risk factor for breast cancer

• Wrensch, et al: landmark study published in 1992 – 2701 women followed for average 12.7 years– Prospective, self-referred women free of BC– Women with atypia = RR of 4.9x

Clinical Validation for HALO

• Numerous additional studies confirm importance of atypia – Wrensch (2001)1, Baltzell (2008)2

– >8800 pts total, > 20 years follow up• Some studies indicate increased risk with presence of cells alone in

NAF – Buehring (2006)3: 972 women followed for mean 25 years– Epithelial cells in NAF = 1.92 RR of invasive BC compared to

women with no NAF or NAF without epithelial cells– Risk increased in patients <55 years

1Wrensch, et al, J Natl Cancer Inst. 2001 Dec 5;93(23):1791-8, 2Baltzell, et al, BMC Cancer. 2008 Mar 19;8:75,3 Beuhring, et al, Breast Cancer Res Treat. 2006 Jul;98(1):63-70. Epub 2006 May 10.

Atypia studied in both high risk and asymptomatic populations relative risk increased in both

Clinical Validation for HALO

• HALO specifically studied in asymptomatic, normal risk women (n=500, avg. age 41) and results published*– Outcomes consistent with earlier studies

• % NAF production • Presence of atypia• Fits within modern risk assessment models

– Very well tolerated by women

• Multiple, peer-reviewed, accepted and presented posters at various specialty meetings demonstrating clinical utility, adoption by OBGYN and Surgical community– NCBC: National Consortium of Breast Centers

– ASBS: American Society of Breast Surgeons

– ASBD: American Society of Breast Disease

– NPWH: Nurse Practitioners in Women’s Health

* Proctor K, et al Cytologic features of nipple aspirate fluid using an automated non-invasive collection device: a prospective observational study BMC Womens Health. 2005 Aug 3;5:10

• ACOG recognizes that Ob/Gyns play the pivotal role in the diagnosis and treatment of benign breast disease and in the reduction of mortality from breast cancer.

• ASBS recognizes the importance of cell based risk assessment and the association of increased risk with atypia

Recognition by Specialists of Need for Risk Assessment in Breast Cancer

• NEJM advocated the use of cost-effective and accurate screening methods to lower the burden of BC

• AIM conclusion: “We can improve primary and secondary breast cancer prevention effectiveness by implementing risk assessment in primary care and mammography facilities and providing tailored recommendations for prevention based on individual risk.”

Recognition by Specialists of Need for Risk Assessment in Breast Cancer

• USPTF: Breast Cancer Screening Guidelines: Annual Screening for average risk women starting in their 40s

• Women at average risk* are:– Without preexisting breast cancer – And not considered to be at high risk for breast cancer

• On the basis of extensive family history of breast or ovarian cancer• Other personal risk factors, such as abnormal breast pathology or

deleterious genetic mutations.

• In response to the backlash, the USPTF posted the following:

"So, what does this mean if you are a woman in your 40s? You should talk to your doctor and make an informed decision about whether mammography is right for you based on your family history, general health, and personal values."

Diana Petitti, MD, MPH , Vice Chair, U.S. Preventive Services Task ForceNovember 19, 2009

* http://www.ahrq.gov/clinic/uspstf09/breastcancer/brcanup.htm

Why offer patients Risk Assessment in addition to Screening?

• “Family physicians play a pivotal role in cancer control by identifying those individuals whose behavior, environment, and/or heredity place them at increased risk for developing cancer”1

• Patients are interested in risk assessment: 50% of PCP’s surveyed report patients initiate conversations about breast cancer risk2

• Only 18% report using Gail risk or other “complete” risk assessment, other than family history2

• Risk Assessment is a service available for patients who are MOTIVATED to go above and beyond minimum standards of care and can include known risk reduction strategies

How do we identify the patients at higher risk to

put them on an appropriate care path?

1 Tyler, Snyder ,J Am Board Fam Med. 2006 Sep-Oct;19(5):468-772 Guerra, Sherman, J Am Board Fam Med. 2009 May-Jun;22(3):272-9

Identify Your High Risk Patients

Focus limited resources on the right women

Risk Assessment using HALO

• Atypia is an elevated risk factor for breast cancer (4-5x), validated through decades of study in > 20,000 patients

• HALO offers a non-invasive, well-tolerated method for obtaining NAF, facilitating cytologic evaluation for atypia

• Patients want to understand their risk, and proactively manage their health• Clinical community supports individualized risk assessment and improved methods

for screening and managing risk• HALO offers a clinically-validated, cost-effective, practice enhancing tool for

improving individual BC risk assessment (combined with risk models and standard of care)

• HALO can help you get your patients on the right care path sooner

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