Many patients share the belief that if there is no family history for breast cancer, then their risk for breast cancer is low. This is simply not the case. The facts are worth reviewing to understand and share with patients who may not clearly understand their individual risk for BC. REVIEW BULLETS 1-3 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 25-55 is breast cancer The US Preventive Task Force recommendation in late 2009 has highlighted, in particular, mammographic screening for BC. And the recommendations from that group have been widely rejected by the clinical community and alienated BC advocates and survivors. However, a good outcome of this debate has been to highlight the advances and the limitations of mammographic screening – particularly for the population of women between 40 and 50. REVIEW BULLET 4 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 Advances are needed to help identify women at higher risk for BC, particularly in populations where mammographic screening may be less reliable, or become unavailable through policy or practice changes. The presence of atypia has been long studied and proven to be a significant risk factor. REVIEW BULLET 5 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 We want to highlight the science behind the discovery of atypia through collection of NAF and the opportunity to leverage this science to address an unmet clinical need and identify those patients are higher risk for BC.
The cervical pap test for screening of cervical cancer has had a dramatic effect on mortality over the > 60 years since it’s introduction. The same principles used to detect abnormal cells in the cervix were discovered in 1958 to apply to fluid collected from the breast ducts. Although screening mammography has helped advance the reduction in mortality from BC somewhat, there remains opportunity improve the prevention of, detection of, and reduction in morality of breast cancer. The use of NAF to detect pre-malignant conditions can help address this unmet clinical need.
In reviewing the biology of atypia, genetic mutations impart a growth advantage. While it is not widely agreed that atypical cell proliferation follows a linear progression from normal to hyperplastic, to eventual invasive carcinoma, it is agreed that SOME breast cancers behave in this manner. Furthermore, the “field effect,” now being demonstrated through advanced imaging modalities such as MRI and PET Mammography, exists at the molecular level. The &quot;field effect&quot; in carcinogenesis, in which a seemingly normal epithelium is the result of the clonal expansion of a genetically abnormal clone, has been documented in colon and lung cancers. The literature is dotted with reports of the harboring in normal breast tissue of mutations, including TP53 mutations, Her2 amplification, loss of heterozygosity, and mitochondrial mutations. There is even some evidence that these mutations are associated with susceptibility to disease. (Lui, Stromal Effects in Breast Cancer, N Engl J Med. 2007 Dec 20;357(25):2537-8) If we can identify atypia at the cellular level which is a reflection of changes on the molecular level, there is opportunity to leverage the advances in breast cancer prevention.
Some benign breast disease and certainly atypical breast disease predicts risk to all breast tissue (the commonly accepted concept of field effect which is the idea of generalized risk applicable to all breast tissue because of genetic and/or environmental insults.) The field effect is why prevention modalities like chemoprevention works for both breasts, even when disease is identified in only one breast….) This is a visual demonstration using color enhanced MRI of the field effect. Tissue sampling is a common way to determine these important biomarkers but…. But it’s important to recognize that tissue sampling (biopsy) has inherent error and can only detect conditions like atypia, if they are easily identified on imaging, and furthermore, captured within the biopsy sample.
So is histologic atypia equivalent to cytologic atypia? Isn’t tissue better than fluid? Yes for DIAGNOSIS. Studies since the 1950’s have shown that cytology from nipple aspirate fluid is not a good diagnostic — it does not have a good enough sensitivity for detecting the presence of breast cancer, although in rare cases NAF can demonstrate cancer. However, studies following patients over time have shown that atypia is a significant risk factor for future development of breast cancer. Atypia is present and easily interpreted in NAF . Cytology does examine architecture (similar to histology) which helps define atypia -- this is mostly helpful for the trained pathologist/cytologist to identify atypia. “ From the standpoint of risk stratification, however, cytologic atypia seems to be comparable with histologic atypical hyperplasia. “ From Risk Assessment Working Group—Hollingsworth et al” - this is demonstrated in the next slide.
Multiple studies, 4 highlighted here, have been conducted to prove that atypia confers an increased risk for breast cancer. Two of those here involved histology, and two involved cytology. All 4 studies demonstrated similar relative risk for atypia, supporting the equivalency of histologic and atypia. 20,000 Patients in Multiple Studies 20+ Years Follow-Up Nearly 100 Peer Reviewed Publications NCI, ASBS, ACOG Recognize Importance of ADH The obvious difference in the different methods is the invasiveness of biopsy versus collection of NAF. Furthermore, biopsy doesn’t address the “field effect” problem, whereas NAF collection offers the opportunity to collect cells from multiple ducts.
Generally, patients frequently think of family history as their primary risk factor for breast cancer. However, gender and age are the primary risk factors for breast cancer. In addition, multiple risk factors are at play, which play a role in a patient’s individualized risk for BC. Some of these risk factors are identifiable and quantifiable, such as genetic mutations and parity, however, many remain under study and will be defined with more research over time, such as lifestyle, and hormone use. A review of some specific risk factors can illustrate where tissue risk falls. (next slide)
As this chart shows, risk factors that may be shared by nearly all patients such as age at menarche and alcohol consumption confer slightly elevated risk. Family history also confers elevated risk, but not the to extent that most patients assume. Prior invasive cancer and LCIS/DCIS ( when known ) obviously confer a greater risk. But look at the position of atypia within the risk stratification: higher than family history and nearly as high as prior invasive cancer. This is the relative risk for cytologic atypia. Histologic atypia (through prior breast biopsy) is slightly higher at 5.3x, but a biopsy presumes presence of a lump or abnormality, whereas cytologic sampling can occur in asymptomatic women.
Quantitative risk models for breast cancer risk prediction began with the Gail model which includes primary family history (material 1 st degree relatives only), age at menarche and parity, and previous breast biopsy (regardless of diagnosis). The Gail model was first published in 1989 and has been updated over time. Other models have been developed, such as the Claus Model (best known for incorporating paternal history) and the Tyrer-Cuzick model, which incorporates primary and secondary family history, and personal risk factors, like atypia, along with some other ethnic risk factors. All of these models have been studied and validated. Quantitative risk assessment tools are invaluable to the clinician because they yield estimates of the probability that the patient will develop breast cancer within a defined period of time and, if helpful, over a lifetime. This temporal framework helps make the level of risk real and understandable to the patient. However, shortcomings of these population-based risk models include over and/or under-estimation of risk based upon a patient's individualized risk. The use of NAF cytology can help identify a significant risk factor – atypia – in asymptomatic women, and in a population of women who are either not undergoing any type of screening, and where risk assessment using models, may poorly estimate her individual risk.
Standard of care screening currently includes clinical breast exam, mammography in women > 40 (variable compliance) and MRI only in high risk patients after negative mammogram. This tool, while powerful, is only used in a limited patient population and is not a standard screening tool. All methods for screening yield 1% or less for detection of breast cancer. Despite the US Preventive Task Force recommendation against self and clinical breast exam, the clinical community continues to believe in the value of women, and their doctors, in performing this exam, as currently, it serves as the only type of screening for asymptomatic women who are not yet receiving mammograms. Use of NAF offers another method to help stratify risk for these younger, asymptomatic patients.
It’s important to recognize that screening for risk factors occurs in many aspects of a patient’s health care. Cholesterol testing is one such common example. One evaluating a patient's cholesterol levels, you are not identifying that a patient has cardiovascular disease, but rather, what her risk may be for developing cardiovascular disease so that intervention may occur, if it is needed to ward off disease progression. Likewise, identifying atypia through NAF is similar. You are helping an asymptomatic woman identify an important risk factor for breast cancer as part of the overall risk assessment. Then you can stratify her into a care path that is appropriate for her state of health.
An important concept in BC risk assessment is that it is fluid. A patient’s condition, and her risk, changes over time, and new information can change her care path. Comprehensive risk assessment, therefore, must include the use of quantitative risk models, periodically (recommend: annually) along with offering her the latest advancements in risk assessment, which are being developed rapidly. One such advancement is the use of NAF screening using NeoMatrix HALO.
The use of NAF cytology enables the physician to distinguish cellular characteristics in NAF that may indicate risk before a solid lesion appears on self or clinical breast exam or imaging. While there is no defined timeframe for cellular progression, it is generally believed that cellular changes that are precursors to invasive cancer exist up to 8 years prior to the appearance of a detectable mass. The use of NAF, and HALO, is an attempt to stratify some of the 70% of women with no known risk factors who may have an important risk factor for breast cancer, but who does not yet know it.
It’s important to recognize that we, as clinicians, with the current state of the art, see only the “tip of the iceberg” when it comes to breast cancer. We see palpable or imaging detected masses, which are generally invasive by the time we detect them. Advances, including imaging (although not used widespread for screening) and use of NAF cytology, enable us to look beneath the surface to identify potential malignancies before they present through conventional imaging. NAF is a currently available, non-invasive, and cost effective method of identifying this “submerged pathology.”
HALO, developed, by NeoMatrix, is FDA cleared and indicated for the collection of NAF for cytological evaluation in the determination and/or differentiation of normal vs. pre-malignant cells. It has been used in OBGYN, PCP, and breast specialist offices in over 60,000 procedures and has a small footprint, enabling easy storage and movement within the office.
Technology acquisition is easy with multiple options to obtain the system. A NeoMatrix representative can discuss these. Further of interest to doctors is that, after training, a nurse or medical assistant can perform the test, so your presence is not required during the test. Currently, performing the test is not covered by 3 rd party payers, but the single patient use disposables are inexpensive (~< $25 each) enabling a practice to offer the test at a reasonably low cost to the patient, generally between $75-150 (determined by the practice). NeoMatrix can provide you a proforma to help you identify the return on investment timeframe and revenue modeling for your practice. Many practices have reported using the additional income obtained from offering HALO to offset the ever increasing insurance premiums, the addition of a medical assistant, or addition of other technological advancements for patient care. In short, using HALO can not only help you offer an important test to a patient to help her, and you, understand her BC risk, but can also enhance your practice.
HALO is a quick, well-tolerated test. It’s principles are similar to that of a breast pump used by nursing moms, if that helps you to describe it to your patients. Once fluid is collected (in ~ 50% of cases, patients will yield fluid), it is processed in a manner similar to that of a cervical pap. If you so choose, trained labs can be recommended by the company to process the samples, but the company can also work with your pathologist/cytologist to train him/her in evaluating HALO samples.
As mentioned, ~ 50% of patients will not yield fluid. This means that these patients are at “normal” risk for BC. She is not at a reduced risk. Recall, however, that risk assessment is fluid and annual HALO is recommended, just like annual pap and wellness exams. Patients who do produce fluid may have acelluar fluid, or cells with no atypia. For the pathologist, his is similar to a thyroid FNA where obtaining and interpreting acellular samples (or 10 or fewer cells) is common. These patients are at a slightly elevated risk (1.7-2.8x) and should be annually monitored to detect any changes. Patients who show cells with atypia should be evaluated according to the following care path.
Acellular or normal cell samples should be followed annually, or if hyperplasia is identified, possibly referred to a breast specialist, after discussion with the patient. Many studies have indicated a 2x or close to 2x risk associated with hyperplasia finding in NAF. Seeing these patients and following up with them is a local/regional care path preference. Some breast specialists want to see and evaluate these patients, some want them followed by their OBGYN or PCP and tested for changes. Fluid with atypia confers elevated risk and this offers the opportunity to refer the patient to your partner breast health specialist and facilitate her care as a higher risk patient. NeoMatrix can help you identify a breast surgeon or specialist in your area if you need to find a partner who will employ the most state of the art risk assessment recommended by breast specialists.
We are learning more all the time about prevention and risk reduction, but current studied and understood risk reduction strategies include these listed. SERM intervention “threshold numbers” are based upon quantitative risk models such as Gail, Tyrer-Cuzick and the NSABP P-1 Breast Cancer Prevention Trial study. The success of that trial in achieving a 49% risk reduction in the development of breast cancer reinforced the utility of objective measures of risk. (Hollingsworth, Am J Surg. 2004 Mar;187(3):349-62. Review) It’s important to note that lifestyle changes can not only help a patient reduce her risk for breast cancer, but other types of cancer and disease as well .
You might wonder if collection of NAF and a “normal” test result rules out breast cancer. The answer is not any more so than the current risk assessment and/or screening methods used. Recall the yields on routine screening is currently ~1%. Detection of atypia in NAF is also ~1%, consistent with these other methods. HOWEVER, it is currently the ONLY method that can be used in asymptomatic women (besides CBE) and those who are not yet eligible for mammographic screening, or in whom mammographic screening is less reliable (dense breasts, etc.) Furthermore, atypia is a proven, studied, and validated risk factor. HALO offers a well-tolerated, non-invasive method for collecting NAF, and obtaining a valuable piece of risk data for a patient that is otherwise not obtained.
The use of NAF and detection of atypia is not new science. As early as 1958, Dr. Papanicolaou (of the “pap test”) identified that NAF cytology could convey important information about the state of breast health. Since the early 1970’s, this concept has been studied in tens of thousands of women – both high risk and normal risk. All of the studies verify that presence of atypia – detected both through histology and cytology – conveys an elevated risk, of about 5.0x, for the development of breast cancer.
The use of NAF and detection of atypia is not new science. As early as 1958, Dr. Papanicolaou (of the “pap test”) identified that NAF cytology could convey important information about the state of breast health. One study showed that the presence of epithelial cells alone (without the presence of atypia) conferred an elevated risk of 1.92, compared to women who don’t produce NAF, or produce NAF that is acellular and this risk is increased in patients who are younger than 55. Since the early 1970’s, this concept has been studied in tens of thousands of women – both high risk and normal risk. All of the studies verify that presence of atypia – detected both through histology and cytology – conveys an elevated risk, of about 5.0x, for the development of breast cancer.
Specifically, NeoMatrix HALO has been studied as a modern method to obtain NAF, which is easier, better tolerated, and less time consuming than prior methods used. Results, as shown, are consistent with the prior studies and demonstrates HALO as a valuable tool to use with modern risk assessment methods and models. HALO simply automates and more consistently applies the Sartorius method which was the method used in the previously referenced studies. You may recall the use of ductal lavage to collect NAF and we want to mark the distinction between collection of NAF using HALO and that of ductal lavage. First of all, ductal lavage required the use of a microcathether that was inserted into the nipple. It was not well tolerated by women. It was a time consuming procedure for both the patient and the clinician. Lastly, most studies were done on high risk women, not asymptomatic, normal risk women. These are important distinctions to make when you think about the collection of NAF – both for your practice and for your patients who may be familiar with ductal lavage. Although ductal lavage studies provided important data to the clinical community relative to the importance of NAF and risk associated with atypia, the collection using HALO is very different from that using ductal lavage. HALO is well tolerated, quick, can be done by nurse or MA, and is cost-effective. And it is done on asymptomatic patients during an annual wellness visit. The HALO system has been used in > 60,000 procedures and studied by individual practices who have had posters peer reviewed and accepted at recognized national specialty meetings. Should you be interested in joining a study, NeoMatrix can discuss their clinical programs with you.
Even before the controversy of last fall regarding mammograms, specialists recognized the important of their role in the recognition, and treatment of breast disease. The OBGYN and PCP are often the only practitioners a women is seeing for her breast health, and use of the best knowledge of breast cancer risk assessment must begin here. The American Society for Breast Surgeons in 2003 recognized the valuable role of cell based risk assessment and the increased risk of atypia for the development of breast cancer, validating the decades of science performed on this subject.
Since the USPTF recommendations, there have been responses from a myriad of groups emphasizing the importance of cost effective screening and the increasing role that individual risk assessment will play in detecting and treating breast cancer.
Further, the very group who recommended screening mammography for women > 50 included a statement emphasizing the need for annual screening for women in their 40’s if they have personal risk factors, including abnormal breast pathology. Given the backlash, it’s unlikely that clinical recommendations will change, but patients are confused and upset at the information and misinformation resulting in this task force recommendation. This is an important time to discuss individual risk assessment and your role in helping your patient in assessing her BC risk. HALO can be a part of that assessment.
Why do risk assessment at all? Patients want it. Breast cancer is well publicized and most women and men have been in some way touched by the disease. In an environment of increasing emphasis on prevention and wellness, patients want to know what they can do to maintain their health. They do this through information. High volume practices leave little time for traditional breast cancer risk assessment. How can we triage high risk women from primary care to appropriate referral receptacles? HALO offers another, valuable piece of information to the patient.
With limited time and resources and mounting pressure to do less in some regards, in a busy practice, how do we identify the high risk patient and do more? How do we determine who can benefit from further screening, and specialist care? How do we best use limited and specialized resources in health care, now and in the future? The answer lies in comprehensive risk assessment and can be as simple as the annual addition of a quantitative risk model and HALO to your current exam regimen.
Atypia is a proven, studied, elevated risk factor. Outside of breast biopsy, only indicated for symptomatic patients, HALO is the only method for identifying atypia in the asymptomatic patient – the 70% of your patients who have no KNOWN risk factors for breast cancer. The clinical community is driving individualized risk assessment, and breast health starts with the PCP or OBGYN. HALO is well tolerated, cost effective and can offer an advancement to your patients, distinguishing your practice and care. The valuable data obtained from HALO can help you refer your high risk patients to a specialize for further evaluation.
NeoMatrix Introduction to Risk Assessment using NAF and HALO
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 all breast tissue , independent of where an abnormality is discovered Blue = normal Green = 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
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—2004 Slide 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 -
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.
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
1 Wrensch, et al, J Natl Cancer Inst. 2001 Dec 5;93(23):1791-8, 2 Baltzell, 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
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 Force November 19, 2009