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Executive Summary

And it's still certainly American Cancer Society's perspective it's still important to remember that mammography is critically important as part of a screening process. However, we can't stay fixed in time. We have to be open to new ideas. We have to take that information. We have to look at populations.

And again, Dr. Olopade mentioned and Dr. Esserman mentioned, looking at all women to understand what is going to be the best course forward for each of them and trying to tailor our efforts so much more than we've been able to, to this point in time. Well, Dr. Len, you just answered my next question, but I'm going to ask it anyway.

So the American Cancer Society obviously on board with this, and it's important, and you're very interested in it. Yes, we are. And we've been fortunate to be part of it right from the very beginning from Dr. Esserman being a force of nature, shall we say, who had an idea and took it forward, and I think deserves a tremendous amount of credit for the work that she's done and the leadership she's provided. But I come back to the point I made a moment ago-- you can't stay still in science. We doctors-- it takes us a long time to change anything.

I mean, somebody once said it was 17 years from a new discovery to actually making it work, unless there's a big financial piece, but we won't get into that discussion. Yes, I firmly believe on a very personal level that we need to entertain new ideas. It doesn't mean we abandon what we have so far because we still are accumulating evidence. And evidence is key to understanding how to best move forward. There's a new thing in medicine that started taking hold, and certainly the folks here at University of Chicago know it as well as anyone else.

Sometimes less is more. And being able to tailor the needs to the person at hand is critically important in health care. We're all beginning to recognize that. And when you think about mammography, when you think about breast cancer screening, when you think about all of the things that can happen to a woman who gets a mammogram, it's important to understand and make sure that we're giving her the best advice and the best opportunities possible.

Now, I do want to encourage people to go ahead and type your questions in. We're already getting quite a few questions from viewers. So we'll get to as many of those as possible. And I want to just throw out a couple of those if that's all right and we can get to those. The first question is, is this open to women of all ages? So this study actually is starting with women 40 to 75 because that's the ages at which we are recommending screening now.

As Funmi was talking about earlier is that one of the things that we may learn from this is that there are certain groups of people where we should start earlier. And if it turns out that the incorporation of the genetic background on every patient is important, that's something you can do at age 25 and when you go to implement it.

But for now, we're starting this study for women 40 to But what I really would hope will be a secondary effect of this study is that everyone starts talking about what's my risk for breast cancer? When should I start screening? And if we all begin to have that conversation with our doctors and if women who participate in the study talk to other women, then we have a whole movement of women asking the question, what's my risk and when should I begin screening?

And what should I do about it? And there's more than just screening that you can do about it. One of the things that we want to know is if you are at higher risk, there are things that you can do to lower that risk, and it depends on what there-- but we've spent hundreds of millions of dollars on prevention research, and we apply very little of it. Just like you know everyone knows about risk for heart disease, the Framingham study, think about the WISDOM Study as starting out as the Framingham study or just the beginning of applying that and trying to get it into common practice, where that's something that you would do.

What's my risk for breast cancer? What should I be doing about it? How can I tailor it? What kind of cancer am I at risk for? All of that-- this is what this study is going to lead us to. I'm going to come back to a comment that Dr. Olopade made, which I think is actually personally incredibly important. And it's not always about the fancy science that we need to know about, it's the fundamental things we need to know about ourselves.

So I write a blog periodically, but started back in the mid s when my first blogs was about the importance of family history. And here I am still writing about the importance of family history. Yes, we have blood tests or we have other forms of testing that we can do to look at our risk, but before we get there, we should all know what our family history is.

And we should have doctors, and other health professionals, clinicians who understand the importance of that. I can't tell you the number of times I've talked to people who have been treated at major centers who have not even had their family history examined. So there's a place to start and we can all do that easily. And the reason why we really love having Dr. Len on this panel is that you know can get your risk from your father's side.

Because every time we're talking about breast cancer, women only think, oh, I can only think about whether my mother had breast cancer.

1st Edition

You need to know about your mother and father. Fantastic point. And one of the reasons why we incorporated the spit test with Color is because in fact, some people also don't know their family history because they're adopted or they come from small families. And easier even than asking-- I mean, you should know your family history because that could add additional information and help us learn even more. But if we can pretty easily today-- you know, we have a partnership with Color Genomics who is helping us with the study.

If in fact for the price of a mammogram, you can get all of that genetic information, my goodness, why don't we have it? And why don't we find the people at highest risk for breast cancer and do something about them?


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And maybe over the course of the study, we'll learn that the people with the lowest risk don't need as much screening or screening at all, like we do with colon cancer. Now, we have again, several questions coming in. One of the questions is where can I learn more about this study to see if I'm eligible?

And I think we do have a graphic we can put at the bottom of the screen. Its wisdomstudy. That's correct. There we go. Pop that up, and just go there, and you can learn about the study and even sign up, I believe. Is that correct? Yes, you can just go in and sign up. That's fantastic. Another question from a viewer-- is the study restricted only to Chicago? I know the answer to that because we have people not from Chicago here, but go ahead and kind of tell how that works. So we started this study in California. At the first, we started with a partnership with the University of California Medical Centers.

And we soon realized that we needed to really make it available to people across the state. And then the Sanford Health in the Midwest joined us and they have made their network of hospitals eligible. And then we have this fantastic opportunity to partner to spread this across the country with Blue Cross Blue Shield Association. This is actually a really important part of the study. And I actually really applaud Blue Cross Blue Shield for stepping up and saying, look, everyone has a responsibility to generate the information that will help women know how to get the best care.

And I think all insurance companies should step up because this, in fact, is a very cost effective way because it helps us apply our resources in a smart way. And the genetic testing, which is a part of it, is covered. And the way we do this is covered. And we have additional partnerships where we're working on getting broader aspects. And we hope that shortly, all of the insurance companies will step up and follow Blue Cross Blue Shield's lead. And one of the things that's really exciting about this moment in time is that we have a National Cancer Institute that's been really focused on what we call the cancer moonshot.

We're really talking about we have some things that if we implement it right now, we can cut cancer death rates just by doing what we know we're capable of doing. And so having a study of , women is an opportunity for us to partner with insurance companies, to partner with institutions like ours because we have a new program-- a specialized program of research excellence in breast cancer. And one of the things we are focused on is trying to reduce cancer health disparities. Why is it that we have such a huge gap between those of us who work in academic centers and those who practice in community centers in terms of when our studies actually get to the community?

Now with our transnational research enterprise, with the NCI funding us and saying get the studies out of there, make sure clinical trials are accessible in the communities, we hope that more insurance companies will come to the table, that more community hospitals will come to the table, and that we can answer these questions together. You know it's interesting. I want to follow up on what you just said. It's a question I was going to ask you later in the show, but I think it's appropriate here. Why is there such a discrepancy or difference in screening for women of color, immigrant women, and different socioeconomic status women?

Why is there such a difference and what can we do to solve that because obviously, it makes a huge difference? So one of the things that is happening in medicine is that we're actually looking at health systems. So we want to do personalized screening and we want every woman to have the opportunity to say, what is my risk for cancer?

Well, imagine if a woman actually wants to do that, but the health system doesn't allow her to do that. Where does she go? So one of the things we've found in going to the communities on the south side of Chicago was that there was actually no access to mammography. People wouldn't know. Even if they wanted it, they couldn't get one. And so part of what we really want to do with this movement is to not only say a woman should know about their risk, but that we transform the health care system so that health systems will begin to manage the health of their population.

They'll be able to remove any barrier to a woman getting the care that she needs. If a woman needs a lot more care because they have a high risk, then figure out how to get them there. And if they don't need as much risk, then figure out how to support each woman in the community in which they live. And that's why , women is actually not enough, but we have to start somewhere. Tim, let me expand that just a little bit because I think there is an important point that has to be made.

And what was interesting about that study was in those cancers where we can screen and institute early detection techniques, there were big gaps based on where you live. And that could be related to socioeconomic. It could be related to education. It certainly is related to access because we have to make sure that every person-- and in this case, every woman-- has access to the best medical care possible, no matter where they live in the country because these differences are not inconsequential.

Well, and these differences, it is a matter of life and death. Well, you know I think that you had asked before, why doesn't everyone just agree? Why isn't it so simple? Why not just screen everybody all the time? You know, I think this is the classic question. And it turns out I think it's important, especially when you have communities that don't have enough resources, you want to be smarter about how you use your resources.

And I think it's important to know that screening has there's good sides of screening and there's downsides to screening. And you know sometimes when we call people back, we do a lot of biopsies, a lot of these biopsies turn out to be nothing. But until you get that answer, you think, oh, my gosh, I'm dying of breast cancer. Or if I find a cancer that turns out to be not that aggressive, and I give people a very aggressive treatment, then I might have done more harm than good.

So really the opportunity for us to start figuring out who needs what and how we can apply our resources so the most people get the most good-- that's what we want. And that it is we talk about access. If we know which populations to focus on, we can really make that a criteria. And if we know for whom early prevention-- really figuring out how to turn the processes along or the people with the very highest risk to do preventive interventions-- that would do the most good for everyone.

But so it all has to be integrated and we have to roll this out in a way that we can learn and keep learning. And women should demand this. They should demand the iPhone 15 of screening, not be on the old Motorola brick phone-- the handheld phone-- which is sort of where we are now.

And we can't make the data from 30 and 40 years ago better. We just can't do it. It's not better, but we can start today. And every woman can share their wisdom. Everyone can participate and make it better. Can I make another point too going back something. Then I want to get to some more viewers questions. Go right ahead. Real quickly. The comment was made earlier about the insurance companies participating. Insurers spend tremendous amounts of money on treatments because they exist.

And they have to be part of the solution going forward to help determine whether or not those treatments are valid. We have spent decades in some diseases offering treatments that we now know, literally 30 years later, were not as effective as we thought. And so whose responsibility is it to get those answers? It's all of ours.

CDC - Genetic Testing for HBOC Syndrome - Gynecologic Cancer Curriculum - Inside Knowledge Campaign

Women should participate. We should be open to new ideas. And the insurance companies should be providing the platform to help us do the best we can and to keep learning. That's everyone's responsibility to change and make the future better. Sounds good. A couple more questions from our viewers. We're getting quite a few actually that are coming in. This one-- and this is kind of a Chicago-based question, but I think it's something that can be answered-- what do I have to do once I'm in this study?

And this question was do I have to come to the University of Chicago? No, you don't. How does it work. Actually you sign up online. You just watch the video. So there's two things. The first thing that we ask you is if you're willing to participate, we explain about the study. And in fact, we have you can be randomized between the annual screening and the personalized screening.

That's an important way in which we learn. But if you're not comfortable with that and you feel strongly that you want to choose one or the other, go ahead and do that and you can be in our observational arm. And you can participate that way as well. Once you're in an arm, you'll get a screening assignment. If you're in the personalized arm, you'll get a little spit kit that comes to your house, and you spit in it, and you send it back. It takes a month or two to get all the data together. And we get your mammogram, we'll get your density, put all that information together.

And then if you signed up on your phone, you can do it on your phone. You can go to a computer in a library, in a kiosk at the University of Chicago, or at Ingalls Memorial Hospital, or wherever you happen to be. If you're traveling somewhere, you can do it on your phone. So really, it's just a matter of participating. You go get your mammograms where you would normally get them. And we send you questionnaires like every year. And if we think that you're at very high risk for your age group, we're going to call you, and we're going to reach out to you, and we're going to offer you options for reducing your risk-- talking about lifestyle, talking about options for prevention, places nearby where you live to go.

So think of this as concierge for breast health medicine. You make it pretty easy. Very easy, very easy. Yes, wisdomstudy. It's easy. BRCA pathogenic variants also confer an increased risk of fallopian tube and primary peritoneal carcinomas. One large study from a familial registry of carriers of BRCA1 pathogenic variants has found a fold RR of fallopian tube cancer among carriers of BRCA1 pathogenic variants compared with the general population.

Other cancers have been associated in some studies.

The strength of the association of these cancers with BRCA pathogenic variants has been more difficult to estimate because of the lower numbers of these cancers observed in carriers of pathogenic variants. Therefore, at this time, carriers of BRCA1 pathogenic variants should adhere to population-screening recommendations for colorectal cancer. No increased prevalence of hereditary BRCA pathogenic variants was found among Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma.

An initial study based on prospective evaluation of women who tested negative for the BRCA1 pathogenic variant segregating in the family found that five incident breast cancers occurred during more than 6, person-years of observation, for a lifetime risk of 6. Results from numerous other prospective studies have found no increased risk.

A study of women who tested negative for a known familial pathogenic variant in BRCA1 or BRCA2 reported two invasive breast cancers, two in situ breast cancers, and no ovarian cancers diagnosed, with a mean follow-up of 4. Four invasive breast cancers were expected, whereas two were observed.

Although ovarian cancer risk was not increased, breast cancer risk remained elevated. The risks, however, are not equal in all pathogenic variant carriers and have been found to vary by several factors, including type of cancer, age at onset, and variant position. Currently, these SNPs are not being tested for or used in clinical decision making. None of the studies have had sufficient numbers of pathogenic variant—positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management.

In 25 families with BRCA2 pathogenic variants, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3, and 6, Pathogenic variants within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison with families with variants on either side of this region. Ovarian cancer risk is considerably higher in carriers of BRCA1 pathogenic variants, and it is uncommon before age 45 years in carriers of the BRCA2 delT pathogenic variant.

In an Australian study of families with a pathogenic variant in BRCA1 , large genomic rearrangement variants were associated with higher-risk features in breast and ovarian cancers, including younger age at breast cancer diagnosis and higher incidence of bilateral breast cancer. Several studies evaluating pathologic patterns seen in BRCA1 -associated breast cancers have suggested an association with adverse pathologic and biologic features. These findings include higher than expected frequencies of medullary histology, high histologic grade, areas of necrosis, trabecular growth pattern, aneuploidy , high S-phase fraction, high mitotic index, and frequent TP53 variants.

These findings were consistent with multiple smaller series. There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in BRCA1 -associated breast cancer,[ , ] particularly in women diagnosed before age 50 years. A large report of 1, patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified One study examined individuals with triple-negative breast cancer; BRCA1 pathogenic variants were present in Interestingly, a study of 77 unselected patients with triple-negative breast cancer in which 15 In both of these studies, all but one carrier of BRCA1 pathogenic variants received chemotherapy.

If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type BRCA1 may partly explain the aggressive phenotype of BRCA1 -associated breast cancer when BRCA1 function is damaged. The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically and clinically meaningful groups.

There is growing evidence that preinvasive lesions are a component of the BRCA phenotype. A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2 -related tumors than in sporadic controls; however, a single BRCA2 founder pathogenic variant del5 accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation.

Given that germline pathogenic variants in BRCA1 or BRCA2 lead to a very high probability of developing breast cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Ovarian cancers in women with BRCA1 and BRCA2 pathogenic variants are more likely to be high-grade serous adenocarcinomas and are less likely to be mucinous or borderline tumors.

Histopathologic examinations of fallopian tubes removed from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that suggest a premalignant phenotype. Specifically, the distal segment of the fallopian tubes containing the fimbriae has been implicated as a common origin of the high-grade serous cancers seen in BRCA pathogenic variant carriers, based on the close proximity of the fimbriae to the ovarian surface, exposure of the fimbriae to the peritoneal cavity, and the broad surface area in the fimbriae.

The term high-grade serous ovarian carcinoma may be used to represent high-grade pelvic serous carcinoma for consistency in language. High-grade serous ovarian carcinomas have a higher incidence of somatic TP53 pathogenic variant. Given that germline variants in BRCA1 or BRCA2 lead to a very high probability of developing ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease.

Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[ ] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease. Lynch syndrome is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers including cancer of the renal pelvis, ureter, small bowel, and pancreas , multiple primary cancers, and a young age of onset of cancer.

After colorectal cancer, endometrial cancer is the second hallmark cancer of a family with Lynch syndrome. Even in the original Family G, described by Dr. Aldred Scott Warthin, numerous family members were noted to have extracolonic cancers including endometrial cancer. Although the first version of the Amsterdam criteria did not include endometrial cancer,[ ] in , the Amsterdam criteria were revised to include endometrial cancer as extracolonic tumors associated with Lynch syndrome to identify families at risk.

The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[ - ] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.

A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[ - ] although this has not been consistently observed. Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.

Breast cancer is also a component of the rare LFS, in which germline variants of the TP53 gene on chromosome 17p have been documented. Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death. LFS is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma. The term Li-Fraumeni syndrome was used for the first time in ,[ ] and the following criteria, which subsequently became the classical definition of the syndrome, were proposed by Li and Fraumeni in [ ]:.

Subsequently in , Chompret et al. The criteria were as follows:. These criteria were revised in [ ] based on additional emerging data [ , ] as follows:. In , Bougeard et al. The criteria were revised as follows:. In addition, all eight individuals with a choroid plexus tumor had a TP53 pathogenic variant, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 variants were found.

Subsequently, a large clinical series of patients from France who were tested primarily based on the version of the Chompret criteria [ ] included carriers of pathogenic variants from families. Evaluation of genotype-phenotype correlations indicated a gradient of clinical severity, with a significantly lower mean age at onset among those with dominant-negative missense variants With the exception of adrenocortical carcinoma, affected children mostly harbored dominant-negative missense pathogenic variants.

Cumulative cancer incidence by sex for the top four cancers is included in Table 8. Age-specific risks for developing first and second cancers were comparable. With the increasing use of multigene panel tests , it is important to recognize that pathogenic variants in TP53 are unexpectedly being identified in individuals without a family history characteristic of LFS. Consequently, it remains important to interpret cancer risks and determine optimal management strategies for individuals who are unexpectedly found to have a germline TP53 pathogenic variant, while taking into account their personal and family histories.

One cohort study evaluated individuals with a germline TP53 pathogenic variant yearly at the National Institutes of Health Clinical Center using multimodality screening with and without gadolinium. Baseline screening identified a cancer in eight patients 6. PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine.

Pathogenic variants of PTEN are diverse, including nonsense , missense, frameshift , and splice-site variants. Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated. An updated set of criteria based on a systematic literature review has been suggested [ ] and is currently utilized in the National Comprehensive Cancer Network NCCN guidelines.

With increased utilization of genetic testing, especially the use of multigene panels , clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline PTEN pathogenic variants who do not meet these criteria. Until then, whether Cowden syndrome and the other PTEN hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing remains ambiguous. The American College of Medical Genetics and Genomics ACMG suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with 1 adult-onset Lhermitte-Duclos disease or 2 any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome.

Of the 3, individuals recruited and tested, probands 8. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk, melanoma, kidney cancer, and colorectal cancers should be considered part of the cancer spectra arising from germline PTEN pathogenic variants. Although PTEN pathogenic variants, which are estimated to occur in 1 in , individuals,[ ] account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology.

As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral. There are no data that link PTEN pathogenic variants to an increased risk of ovarian cancer. Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. CNS manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum.

There have been multiple subsequent reports of an excess of lobular breast cancer in HDGC families. HDGC is an autosomal dominant syndrome associated with poorly differentiated invasive adenocarcinoma of the stomach presenting as linitis plastica. PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous. However, other organs are at increased risk of developing malignancies. Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance LOH consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene. Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.

No strong genotype-phenotype correlations have been identified. PALB2 pathogenic variants have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations. Data based on families with loss-of-function PALB2 variants suggest that this gene may be an important cause of hereditary breast cancer, with risks that overlap with BRCA2. In a later Polish study of more than 12, unselected women with breast cancer and 4, controls, PALB2 pathogenic variants were detected in cases 0.

Among PALB2 carriers, breast tumors 2 cm or larger had substantially worse outcomes Approximately one-third of those with a PALB2 pathogenic variant had triple-negative breast cancer, and the average age at breast cancer diagnosis was Male breast cancer has been observed in PALB2 pathogenic variant—positive breast cancer families. PALB2 pathogenic variants were detected in 3. Data suggest that the RR of breast cancer may overlap with that of BRCA2 , particularly in those with a strong family history; thus, it remains important to refine cancer risk estimates in larger studies.

Furthermore, the risk of other cancers e. Given the low PALB2 pathogenic variant prevalence in the population, additional data are needed to define best candidates for testing and appropriate management. Until the s, the diagnosis of genetically inherited breast and ovarian cancer syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate de novo pathogenic variant rate in these populations.

Specifically, in this study of patients with sporadic breast cancer, 17 pathogenic variants were detected, one of which was confirmed to be a de novo pathogenic variant. There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several studies or are supported by robust meta-analyses.

The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response. Fanconi anemia FA is a rare, inherited condition characterized by bone marrow failure, increased risk of malignancy, and physical abnormalities. Progressive bone marrow failure typically occurs in the first decade, with patients often presenting with thrombocytopenia or leucopenia. Given the widespread availability of multigene panel tests , genetic testing of many of the FA genes is frequently performed despite uncertain cancer risks and the lack of available evidence-based medical management recommendations for many of these genes.

FA gene pathogenic variant carrier status can have implications for reproductive decision making because pathogenic variants in these genes can lead to serious childhood onset of disease if both parents are carriers of pathogenic variants in the same gene. Partner testing may be considered. Inactivating variants of BRIP1 are associated with an increased risk of breast cancer. The relative risk RR of breast cancer was estimated to be 2. Of note, in families with BRIP1 pathogenic variants and multiple cases of breast cancer, there was incomplete segregation of the pathogenic variant with breast cancer, consistent with a low-penetrance allele and similar to that seen with CHEK2.

Based on numerous studies, a polymorphism , delC, appears to be a rare, moderate-penetrance cancer susceptibility allele. The ORs and CIs in unselected, familial, and early-onset breast cancer subgroups were 2. However, study limitations included pooling of populations without subgroup analysis, using a mix of population-based and hospital-based controls, and basing results on unadjusted estimates as cases and controls were matched on only a few common factors ; therefore, results should be interpreted in the context of these limitations.

Two studies have suggested that the risk associated with a CHEK2 delC pathogenic variant was stronger in the families of probands ascertained because of bilateral breast cancer. Currently, the clinical applicability of CHEK variants remains uncertain because of low variant prevalence and lack of guidelines for clinical management. A large Dutch study of 86, individuals reported an increased risk of cancers other than breast and colon for carriers of the CHEK2 delC pathogenic variant,[ 42 ] although additional studies are needed to further refine these risks.

Ataxia telangiectasia AT is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. Initial studies searching for an excess of ATM pathogenic variants among breast cancer patients provided conflicting results, perhaps due to study design and variant testing strategies. The Breast Cancer Association Consortium BCAC , an international group of investigators, investigated single nucleotide polymorphisms SNPs identified in previous studies as possibly associated with excess breast cancer risk in 15, to 20, cases and 15, to 20, controls.

RAD51 recruitment to break sites and recombinational DNA repair depend on the RAD51 paralogs, although their precise cellular functions are poorly characterized. The literature, however, has produced contradictory findings. In addition to germline variants , different polymorphisms of RAD51 have been hypothesized to have reduced capacity to repair DNA defects, resulting in increased susceptibility to familial breast cancer. There is significant overlap in the studies reported in these meta-analyses, significant variability in the characteristics of the populations included, and significant methodologic limitations to their findings.

A meta-analysis of 14 case-control studies involving 12, cases and 10, controls confirmed an increased risk only for women who were known BRCA2 carriers OR, 4. In summary, among this conflicting data is substantial evidence for a modest association between germline variants in RAD51C and breast cancer and ovarian cancer. These associations are plausible given the known role of RAD51 in the maintenance of genomic stability. Pathogenic variants in the BRCA1 -interacting gene Abraxas were found in three Finnish breast cancer families and no controls.

Through full exome sequencing among high-risk Polish and Quebec-based French Canadian families, the RECQL gene was discovered to harbor multiple rare truncating variants in both populations. In the same populations, truncating variants in this gene were also identified in two subsequent validation phases among additional breast cancer patients from high-risk families, and among additional breast cancer cases in which the variant frequency was higher than that observed among controls.

A case-control study from Belarus and Germany looked at the most common pathogenic variant, c. The OR in this study alone was 1. Furthermore, the significance of this finding outside of these two populations is not yet known. Small cell carcinoma of the ovary, hypercalcemic type SCCOHT is a rare, aggressive tumor that has an early age at onset before age 40 y and a poor prognosis. SCCOHT tumors may be unilateral or bilateral and have been characterized histologically by the presence of small hyperchromatic cells with brisk mitotic activity.

With a wide range of differential diagnoses including germ cell tumors, sex cord—stromal tumors, and undifferentiated carcinomas, SCCOHT remains classified by the World Health Organization as a "miscellaneous tumor" but more recently has been sequenced to be a malignant rhabdoid tumor. Immunohistochemistry demonstrated loss of SMARCA4 protein expression in seven of nine tested cases, consistent with a tumor-suppressor gene function. In a second study of another 12 patients, next-generation sequencing also identified SMARCA4 as the only recurrently variant gene, with the majority of variants predicted to result in a truncated protein.

There is currently no consensus for management, yet SMARCA4 is on the larger multigene panels currently available for genetic testing, and risk-reducing surgery has been offered to pathogenic variant carriers. Polymorphisms underlying polygenic susceptibility to breast and gynecologic cancers are considered low penetrance , a term often applied to sequence variants associated with a minimal to moderate risk.

Because these types of sequence variants also called low-penetrance genes , alleles, variants, and polymorphisms are relatively common in the general population, their overall contribution to cancer risk is estimated to be much greater than the attributable risk in the population from pathogenic variants in BRCA1 and BRCA2.

The NH variation in BRCA2 , initially thought to be a low-penetrance allele, was not verified in a large combined analysis. Two strategies have attempted to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design.

The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and then searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and, despite some confirmed associations described below , has been relatively disappointing.

The current paradigm uses sets of as many as 5 million SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap and the Genomes Project. Although this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal. Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases,[ 9 ] including breast cancer.

The 8q region and others may harbor multiple independent loci associated with risk. Subsequent genome-wide studies have replicated these loci and identified additional ones. Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. No interaction between the SNPs and epidemiologic risk factors for breast cancer have been identified.

A subsequent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of more than 5, breast cancer cases and nearly 6, controls, using a model with traditional risk factors compared with a model using both standard risk factors and ten previously identified SNPs. Despite this, Whether such information has clinical utility is unclear.

More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of more than 10, cases and 13, controls have been carried out for ovarian cancer. The collective influence of many genetic variants has more recently been evaluated using an aggregate score. In , a polygenic risk score PRS comprising all of the known breast cancer risk genetic variants or SNPs was estimated in women of European ancestry using 41 studies in the Breast Cancer Association Consortium BCAC , including more than 33, breast cancer cases and 33, controls.

Biobank , which incorporates information on genetic variants and is optimized for ER-positive and ER-negative breast cancer. Common genomic variants associated with the development of a first primary breast cancer are also associated with the development of CBC. The authors noted that the incorporation of the PRS into risk prediction models may better inform decisions on cancer risk management for this population.

Several studies have examined the extent to which clinical breast cancer risk prediction models can be improved by including information on known susceptibility SNPs, and reporting improved discriminatory accuracy after inclusion of the PRS. In addition to GWAS interrogating common genetic variants, sequencing-based studies involving whole-genome or whole-exome sequencing [ 48 ] are also identifying genes associated with breast cancer, such as XRCC2 , a rare, moderate-penetrance breast cancer susceptibility gene.

Increasing data are available on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast cancer or ovarian cancer. Refer to the PDQ summary on Breast Cancer Screening for information on screening in the general population, and to the PDQ summary Levels of Evidence for Cancer Genetics Studies for information on levels of evidence related to screening and prevention.

In the general population, evidence for the value of breast self-examination BSE is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China. Little direct prospective evidence exists regarding BSE in individuals with an increased risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives FDRs with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of high-risk women at a referral center, five breast cancers were detected by self-examination less than a year after a previous screen as compared with one cancer detected by clinician exam and 11 cancers detected as a result of mammography.

Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses. Education and instruction in self-examination are recommended. Level of evidence: 5. In this study, the sensitivity was lowest for younger women aged 30—49 y who had a FDR with breast cancer.

Pushing margins, characteristic of medullary histology, are associated with an absence of fibrotic reaction. Both groups were given instruction in BSE. After a mean follow-up of 13 years range, One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE. Digital mammography refers to the use of a digital detector to find and record x-ray images. This technology improves contrast resolution [ 20 ] and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6, examinations of women aged 40 years and older found no difference in cancer detection rates;[ 21 ] however, digital mammography resulted in fewer recalls.

In another study ACRIN comparing digital mammography to plain-film mammography in 42, women, the overall diagnostic accuracy of the two techniques was similar. In a prospective study of individuals with BRCA pathogenic variants who received uniform recommendations regarding screening and risk-reducing surgery, annual mammography detected breast cancer in six women at a mean of Mammograms should be done at a consistent location when possible, with prior films available for comparison.

Certain observations have led to the concern that carriers of BRCA pathogenic variants may be more prone to radiation-induced breast cancer than women without pathogenic variants. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA variant, but this is not consistent and varies by experimental system and endpoint.

Three studies have failed to find convincing evidence of an association between ionizing radiation exposure and breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants. Women exposed before age 30 years had an increased risk HR, 1. This risk was primarily driven by nonmammographic radiation exposure in women younger than 20 years HR, 1. Subsequently, a prospective study of 1, BRCA1 carriers and BRCA2 carriers without a breast cancer diagnosis at study entry, with an average follow-up time of 5.

With the routine use of magnetic resonance imaging MRI in carriers of BRCA1 and BRCA2 pathogenic variants, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women. Because of the relative insensitivity of mammography in women with an inherited risk of breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including carriers of BRCA pathogenic variants.

Many studies have described the experience with breast MRI screening in women at risk of breast cancer, including descriptions of relatively large multi-institutional trials. Despite some limitations of these studies, they consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer missed by screening.

Regarding downstaging, one screening study demonstrated that patients at risk of hereditary breast cancer were more likely to be diagnosed with small tumors and node-negative disease than were women in two nonrandomized control groups. Six cancers were first detected on MRI; three were first detected by mammogram; and two were interval cancers. All breast cancers occurred in carriers of BRCA1 pathogenic variants, suggesting a continued high risk of BRCA1 -related breast cancer after oophorectomy in the short term.

MRI-screened patients in the entire cohort were more likely to be node-negative and receive less chemotherapy. An additional question regarding the timing of mammography and MRI is whether they should be done simultaneously or in an alternating fashion so that while each test is done annually, screening occurs every 6 months. Level of evidence: 3. Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review. Nine other biopsies of benign lesions were performed.

One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone. A number of other techniques are under active investigation, including tomosynthesis, contrast-enhanced mammography, thermography, and radionuclide scanning. Additional evidence is needed before these techniques can be incorporated into clinical practice. Risk-reducing mastectomy RRM is a management option for patients who are considered to be at high risk of developing breast cancer.

If the patient is interested, reconstruction can be performed simultaneously with the ablative portion of the procedure. A number of different tissues can be used to reconstruct the breast, including flaps based on the latissimus dorsi muscle, the transverse rectus abdominis muscle, or the gluteus muscle.


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Muscle-sparing techniques such as the deep inferior epigastric perforator flap can also be used, but require advanced microvascular techniques. In the interest of improved cosmetic outcomes, skin-sparing techniques have been utilized in which the entire breast is removed with the NAC, but the entire skin envelope of the breast is preserved.

HBOC Genetic Results Interpretation and Risk Management

In a further refinement, nipple-sparing techniques have been developed in which all of the breast skin and the nipple are preserved while the underlying glandular tissue is removed. Because there are no randomized, prospective trials of RRM versus observation, data are limited to cohort and case-control studies. The available data demonstrate that RRM does decrease breast cancer incidence in high-risk patients,[ 54 - 56 ] but overall survival OS correlates more closely with the overall risk from the primary incidence of breast cancer.

Several studies have analyzed the impact of RRM on breast cancer risk and mortality. In one retrospective cohort study of women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years.

In a follow-up subset analysis, of the high-risk women in this cohort study underwent genetic testing for pathogenic variants in BRCA1 and BRCA2. Pathogenic variants were identified in 18 women, none of whom developed breast cancer after a median follow-up of The calculated risk reduction among carriers of pathogenic variants was The result of this retrospective cohort study has been supported by a prospective analysis of 76 carriers of pathogenic variants who underwent RRM and were monitored prospectively for a mean of 2.

No breast cancers were observed in these women, whereas eight were identified in women who underwent regular surveillance HR for breast cancer after RRM, 0. The rate of breast cancer in carriers of pathogenic variants who underwent bilateral RRM was compared with that in carriers who did not choose surgery.

However, delaying mastectomy until age 40 years, or substituting RRM with screening with breast MRI and mammography, had little impact on survival estimates. The investigators concluded that, compared with surveillance, risk-reducing surgery mastectomy and oophorectomy is cost-effective with regard to years of life saved, but not for improved quality of life.

Level of evidence: 3ai. If RRM is effective in lowering breast cancer risk in unaffected women, what is its role for women with unilateral breast cancer? This question often arises in discussions about surgical options with women who have unilateral breast cancer and hereditary risks. This section addresses the role of contralateral risk-reducing mastectomy CRRM in women being treated with mastectomy and will not discuss breast conservation therapy.

Multiple studies have shown an increase in the rate of CRRM in women with unilateral breast cancer. In the general population, current estimates of CBC risk after treatment for breast cancer are approximately 0. In carriers of BRCA pathogenic variants whose first cancer has an excellent prognosis, estimating the risk of a second, unrelated breast cancer event is important for informing their decision to undergo risk-reducing surgery and has been described in this setting to improve survival.

Therefore, for individuals at increased risk of carrying a BRCA pathogenic variant, it is important that genetic testing be considered in advance of surgery, when possible. Survival was better among women who underwent CRRM, but this result was likely associated with higher mortality caused by the index cancer or metachronous ovarian cancer in the group not undergoing surgery.

No breast cancers occurred in this cohort over the follow-up period, though more than 34 breast cancers would have been expected. A Dutch cohort of patients identified between and , who had both a BRCA pathogenic variant and a diagnosis of unilateral breast cancer, were evaluated for the effect of CRRM. In an attempt to control for the bias of time to surgery, the authors included a separate evaluation of women who were known to be disease free 2 years after the primary cancer diagnosis HR, 0.

Additionally, the group who underwent RRM was more likely to undergo bilateral salpingo-oophorectomy and systemic chemotherapy, which may influence the significance of these survival findings. This was a relatively small study, and although the authors adjusted for multiple factors, residual confounding factors may have influenced the results.

All of these studies are limited by the biases introduced in relatively small, retrospective studies among very select populations. There is often limited data on potential confounding variables such as socioeconomic status, comorbidities, and access to care. It has been suggested that women who elect to undergo RRM are healthier by virtue of being able to tolerate more extensive surgery. Results showed a reduction in all-cause mortality and breast cancer—specific mortality, and also in noncancer event mortality, a finding that would not be expected to be related to CRRM.

The option of nipple-sparing mastectomy NSM in carriers of BRCA pathogenic variants undergoing risk-reducing procedures has been controversial because of concerns about increased breast tissue left behind at surgery to keep the NAC viable.

Hereditary Breast & Ovarian Cancer Risk & Prevention

The ability to leave behind minimal residual tissue, however, may be related to experience and technique. Incidental cancers were found in 4 of RRM patients 2. With a mean follow-up of A study of NSMs performed in 89 carriers of BRCA pathogenic variants between and reported similar, excellent local control rates. Sixty-three patients had risk-reducing NSM median follow-up, 26 months; range, 11—42 months , and 26 patients had NSM and a diagnosis of breast cancer median follow-up, 28 months; range, 15—43 months.

Five patients required further nipple excision. There were no local recurrences or newly diagnosed breast cancers. Level of evidence: 3aii. Individual psychological factors play an important role in decision-making about RRM by unaffected women and CRRM in women with unilateral breast cancer. A Mayo Clinic study of women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups.

A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation. The evidence for the effect of RRSO on breast cancer has evolved. Early small studies suggested a protective benefit. Despite discordant findings regarding RRSO and breast cancer risk in the existing literature, aggregate data suggest that there is a benefit, although the magnitude of this benefit may not be fully understood.

Further prospective studies are needed to confirm these findings. Tamoxifen a synthetic antiestrogen increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The incidence of ER-negative cancer was not significantly reduced. Reductions in breast cancer risk were noted both among women with a family history of breast cancer and in those without a family history.

An increased incidence of endometrial cancers and thrombotic events occurred among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [ 89 ] or 70 months,[ 90 ] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy HRT. Subsequently, the International Breast Cancer Intervention Study 1 IBIS-1 breast cancer prevention trial randomly assigned 7, women between the ages of 35 and 70 years to receive tamoxifen or placebo for 5 years.

Eligibility for the trial was based on family history or abnormal benign breast disease. There was no reduction in risk of invasive ER-negative breast cancer. Level of evidence tamoxifen in a high-risk population : 1aii. These data must be viewed with caution in view of the small number of carriers of pathogenic variants in the sample 8 BRCA1 carriers and 11 BRCA2 carriers.

Level of evidence: 1aii. In contrast to the very limited data on primary prevention in carriers of BRCA1 and BRCA2 pathogenic variants with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small.

Using both retrospective and prospective data, researchers found a significant decrease in the risk of contralateral breast cancer among women who received adjuvant tamoxifen therapy after their diagnosis. This association persisted after researchers adjusted for age at diagnosis and the ER status of the first cancer.

The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality-of-life data demonstrate slight differences between the two arms. Refer to the PDQ summary on Breast Cancer Prevention for more information about the use of selective ER modulators and aromatase inhibitors in the general population, including postmenopausal women. Another case-control study of carriers of pathogenic variants and noncarriers identified through ascertainment of women with bilateral breast cancer found that systemic adjuvant chemotherapy reduced CBC risk among carriers of pathogenic variants RR, 0.

Tamoxifen was associated with a nonsignificant risk reduction RR, 0. Similar risk reduction was seen in noncarriers; however, given the higher absolute CBC risk in carriers, there is potentially a greater impact of adjuvant treatment in risk reduction. The effect of tamoxifen on ovarian cancer risk was studied in carriers of BRCA1 pathogenic variants. All subjects had a prior history of breast cancer; use of tamoxifen was not associated with an increased risk of subsequent ovarian cancer odds ratio [OR], 0. In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy.

One study evaluated risk modifiers among female carriers of a BRCA1 high-risk pathogenic variant. In women with known pathogenic variants of the BRCA1 gene , early age at first live birth and parity of three or more have been associated with a lowered risk of breast cancer. Studies of the effect of pregnancy on breast cancer risk have revealed complex results and the relationship with parity has been inconsistent and may vary between carriers of BRCA1 and BRCA2 pathogenic variants. Level of evidence: 4aii.

In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies,[ ] and at least one study suggests that it may be protective in carriers of BRCA1 pathogenic variants. A second study failed to confirm this association. There is no consistent evidence that the use of oral contraceptives OCs increases the risk of breast cancer in the general population. When patients are counseled about contraceptive options and preventive actions, the potential impact of OC use on the risk of breast cancer and ovarian cancer and other health-related effects of OCs need to be considered.

A number of important issues remain unresolved, including the potential differences between carriers of BRCA1 or BRCA2 pathogenic variants, effect of age and duration of exposure, and effect of OCs on families with highly penetrant early-onset breast cancer. Refer to the Oral contraceptives section in the Chemoprevention section of this summary for a discussion of OC use and ovarian cancer in this population. Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population.

The estrogen-plus-progestin arm of the study, in which more than 16, women were randomly assigned to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits. Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [ - ] or unaffected by a family history of breast cancer;[ , , ] risk did not vary by family history in the meta-analysis. A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not.

Women taking estrogen alone had an OR of 0. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice. In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer.

No data exist regarding the benefit of clinical examination of the ovaries bimanual pelvic examination in women at inherited risk of ovarian cancer. In the general population, transvaginal ultrasound TVUS appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries e.

Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experience with ovarian cancer screening in high-risk women using TVUS with or without CA Ten women developed ovarian cancer; five of the ten developed interval cancers after normal screening results within 3 to 10 months before diagnosis.

Five of the ten ovarian cancers were screen-detected incident cases, which had normal screening results within 6 to 14 months before diagnosis. Only five of ten were stage I or II. Four of 13 screen-detected cancers were stage I or II. Women screened within the previous year were less likely to have higher than stage IIIC disease; there was also a trend towards better rates of optimal cytoreduction and improved OS. Furthermore, most of the cancers occurred in women with known ovarian cancer susceptibility genes , identifying a cohort at highest cancer risk for consideration of screening.

Of the 3, high-risk women screened, were carriers of BRCA pathogenic variants, 49 of whom developed ovarian cancer. The 5- and year survival was A major limitation of the study was the absence of a control group. Despite limitations, this study suggests that annual surveillance by TVUS and CA level appear to be ineffective in detecting tumors at an early stage to substantially influence survival. Level of evidence: 4. Serum CA screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section.

Thus, it is expected that many new ovarian cancer biomarkers either singly or in combination will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes , either in the general population or in women at increased genetic risk. Before information related to emerging ovarian cancer biomarkers is addressed, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker.

The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity i. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.