Risk-reducing Strategies for Women Carrying brca1/2 Mutations with a

Focus on Prophylactic Surgery

Mohamed Salhab; Selina Bismohun; Kefah Mokbel
Posted: 12/14/2010; BMC Women's Health. 2010;10(1) © 2010 BioMed Central, Ltd.
Abstract and Introduction
Abstract
Background: Women who have inherited mutations in the BRCA1 or BRCA2 genes have substantially
elevated risks of breast and ovarian cancer. Mutation carriers have various options, including extensive and
regular surveillance, chemoprevention and risk-reducing surgery. The aim of this review is to provide an up-to-
date analysis and to subsequently summarise the available literature in relation to risk-reducing strategies, with
a keen focus on prophylactic surgery.
Methods: The literature review is facilitated by Medline and PubMed databases. The cross-referencing of the
obtained articles was used to identify other relevant studies.
Results: Prophylactic surgery (bilateral mastectomy, bilateral salpingo-oophorectomy or a combination of both
procedures) has proved to be the most effective risk-reducing strategy. There are no randomised controlled trials
able to demonstrate the potential benefits or harms of prophylactic surgery; therefore, the evidence has been
derived from retrospective and short follow-up prospective studies, in addition to hypothetical mathematical
models.
Based on the current knowledge, it is reasonable to recommend prophylactic oophorectomy for BRCA1 or
BRCA2 mutation carriers when childbearing is completed in order to reduce the risk of developing breast and
ovarian cancer. In addition, women should be offered the options of rigorous breast surveillance,
chemoprevention with anti-oestrogens–especially for carriers of BRCA2–or bilateral prophylactic mastectomy.
Conclusion: The selection of the most appropriate risk-reducing strategy is not a straightforward task. The
impact of risk-reducing strategies on cancer risk, survival, and overall quality of life are the key criteria
considered for decision-making. Notably, various other factors should be taken into consideration when
evaluating individual mutation carriers' individual circumstances, namely woman's age, morbidity, type of
mutation, and individual preferences and expectations.
Although prospective randomised controlled trials concerned with examining the various interventions in
relation to the woman's age and type of mutation are needed, randomisation is extremely difficult and rather
deemed unethical given the current available evidence from retrospective studies.
Background
Breast cancer remains the leading cause of death in women aged 40–55 years.[1] Sporadic breast cancer accounts
for 70–80% of all cases.[2] It is estimated that 5–10% of all breast cancers and 25%-40% of breast cancers
affecting women younger than 35 years of age are attributable to hereditary causes.[2] Furthermore 60%-70% of
hereditary breast cancers seem to arise secondary to germline mutations in the BRCA1 and BRCA2 genes.[3,4]
Notably, ovarian cancer is a relatively rare disease: it affects one in eighty women at some point during their life
time.[5] Hereditary or familial ovarian cancer is linked to many germline mutations, such as PTEN (Cowden
syndrome), TP53 (Li-Fraumeni Syndrome) and ATM (ataxia-teleangiectatica-mutated gene).[6] However,
BRCA1 and BRCA2 gene mutations are found to cause the majority of autosomal-dominant inherited ovarian
cancer.[6]
Histologically, BRCA1-related breast cancers are predominantly of the basal subtype, with predominant
lymphocytic infiltration, and are often more aggressive and associated with negative prognostic factors, as
characterised by numerous mitoses, pleomorphic pattern, poor differentiation and higher proliferation rates,[7–11]
as well as a negative oestrogen and progesterone receptors status.[8,10,12] Moreover, a lack of HER-2 expression
was observed in breast cancer tumours of BRCA1 carriers.[13] On the other hand, tumours associated with
BRCA2 mutations are of a luminal subtype, and tend to be of a positive oestrogen and progesterone receptors-
status; negative HER-2, on the other hand, do not markedly differ from other hereditary or sporadic breast
cancers.[14] DCIS is found to be equally as prevalent in patients who carry deleterious BRCA mutations as in
high familial-risk women who are non-carriers, but ultimately occurs at an earlier age. Interestingly, BRCA
mutations were found in a significant portion of women with DCIS who were presented for a hereditary risk
assessment.[15] Notably, high-grade DCIS is also more common in BRCA1 mutation carriers than in those
patients without any mutation.[16] Accordingly, it has been suggested that BRCA1/2-associated breast cancers
progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as
a part of the BRCA1/2 tumour spectrum.[17]
Clinically, breast cancer is believed to begin at an earlier age in BRCA1 and BRCA2 gene mutation carriers
compared with sporadic cases. The median age of breast cancer onset ranges from 40–50 years in BRCA1 and
BRCA2 carriers compared with 60–70 years in sporadic cases.[18,19] Furthermore, breast tumours in BRCA1/2
carriers are more likely to be bilateral and affect the contra lateral breast at a later stage.[8,12,19] Furthermore,
BRCA1/2 mutation carriers also have a higher rate of pregnancy-associated breast cancer before the age of 50.
[20,21]

Several studies have suggested no significant differences between BRCA-associated breast cancer and non-
BRCA associated breast cancer in relapse-free, event-free, and overall survival.[22–24] On the other hand, other
studies indicate that BRCA-associated breast cancer presents worse survival rates and overall prognosis.[14,25–28]
Inconsistencies in previous studies may be due to limitations in study design: in particular, the studies contain
small numbers of BRCA cases. Additionally, due to the onset occurring at an extremely early age of those
patients with BRCA mutations, it was not always possible to obtain controls which were considered adequately
matched for age. In addition, inconsistencies in previous studies were due to the examination of both BRCA1
and BRCA2 mutation groups together. Lee et al., for example, recently conducted a meta-analysis of 11
previously published articles.[29] The analysis shows that the BRCA1 mutation carriers have worse predicted
overall survival rates (approximately 5 years) than non-carriers (HR = 1.94, 95% CI, 1.45–2.53). Furthermore,
long-term overall survival (10 years or greater) was found to be worse in BRCA1 mutation carriers compared
with non-carriers (HR = 1.33, 95% CI, 1.12–1.58). However, they indicate that there has been no significant
heterogeneity observed across the studies.
Moreover, Lee et al. observes that short-term progression-free survival in BRCA1 carriers was worse than in
non-BRCA carriers (HR = 1.54). Such observations were not witnessed in long-term progression survival. In
addition, BRCA2 mutation was not observed to affect either short- or long-term survival rates, which may be
attributed to the different carcinogenic pathways for BRCA1 and BRCA2.[29]
Most ovarian cancers associated with germ line BRCA mutations are diagnosed at a younger age and are
ultimately determined as high-grade and advanced-stage serous carcinomas.[30] They have surgical and
pathological characteristics similar to those of sporadic cancers. BRCA mutations do not seem to play a
significant role in the development of mucinous or borderline ovarian tumours.[21] Moreover, BRCA1 germline
mutation carriers are not only at risk of ovarian cancer, but also fallopian tube carcinoma and peritoneal
papillary serous carcinoma.[31] Olivier et al. suggest that peritoneal papillary serous carcinoma risk amongst
BRCA2 carriers is lower than amongst BRCA1 carriers.[31] Furthermore, hereditary ovarian cancer has a
distinctly better clinical outcome with a longer overall survival and recurrence-free interval after chemotherapy
than sporadic cancers.[21] Notably, it has been observed that BRCA-positive Epithelial Ovarian Cancer patients
have better outcomes than non-hereditary epithelial ovarian cancer patients,[32] and advanced-stage hereditary
cancer patients survive longer than nonhereditary cancer patients.[33]
The identification of BRCA1 and BRCA2 genes in 1994 and 1995 respectively[34,35] has had a great impact on
the understanding and management of sporadic and hereditary breast and ovarian cancers. Whilst the risk of
breast and ovarian cancer in the general population is 10%-13% and 1.7%, respectively, studies indicate that a
woman with mutations in either BRCA1 or BRCA2 carries a lifetime breast cancer risk of 80% and 20%-60%
for developing breast cancer and ovarian cancer respectively.[3,36] In the case of BRCA1 gene mutation carriers,
the cumulative risk of cancer by the age of 70 years ranges between 51% and 95% for breast cancer, and
between 22% and 60% for ovarian cancer. Similar trends are also observed in BRCA2 carriers, as the risk
ranges between 33% and 95% for breast cancer, and between 4% and 47% for ovarian cancer.[37]
Women who have an increased risk of breast and ovarian cancer are advised to consider risk-reducing
strategies; however, such methods vary in their effectiveness. These strategies include surveillance (breast self-
examination, clinical breast examination, screening using mammography and breast magnetic resonance
imaging (MRI), trans-vaginal ultrasound scanning and serum (CA125), chemoprevention and prophylactic
surgery (salpingo-oophorectomy and/or mastectomy).[38,39] Risk-reducing strategies have been shown to have
associations with a gain in life expectancy in BRCA1/2 carriers. Moreover, extended life expectancy can range
from between a few months to a few years, although this is ultimately dependent on the prophylactic
intervention (Table 1).
The aim of this review is to provide an up-to-date analysis and to subsequently summarise the available
literature in relation to risk-reducing strategies, with a keen focus on prophylactic surgery.
Conclusions
Selecting the most appropriate risk-reducing strategy is not a straightforward task. The impact of risk-reducing
strategies on cancer risk, survival, and overall quality of life are the key criteria considered for making a good
decision. There is no sole risk-reducing strategy which is able to fully meet all expectations and requirements in
an individual woman. On the one hand, non-surgical procedures provide a good body image and quality of life,
but may be associated with increased risk of advanced-stage cancer and mortality; on the other hand, surgery
ensures a very high protection from cancer but is associated with a number of disadvantages of invasiveness,
non-reversibility and surgical morbidity.
Based on the available literature, it is deemed appropriate to acknowledge that the clinical management of
cancer risk in BRCA1 and BRCA2 mutation carriers is a rather complex and stressful task, which should
consider individual patients' expectations and preferences. Such preferences can be informed by accurate
knowledge of the risks and benefits of the interventions considered. Available studies confirm the essential role
of PBSO in reducing the risk of both breast and ovarian cancer. Furthermore, other options for risk reduction
should be considered, such as chemoprevention and risk-reducing mastectomy.[74] Although coordinated, PBM
and PBSO are feasible procedures with acceptable morbidity in selected high-risk patients;[97] the timing of
prophylactic surgery is still a matter of paramount importance to both patients and clinicians to consider during
the counselling process.
It is recommended that prophylactic surgery should be performed as soon as possible, simply because of the
early development of cancer in BRCA mutation carriers. Although ovarian cancer rarely occurs in
premenopausal women, it is advised that BRCA mutation carriers should undergo PBSO immediately after
childbearing is complete in order to reduce the risk of early breast cancer development.
Prospective randomised controlled trials examining the various interventions in relation to the woman's age and
type of mutation are needed. However, the randomisation of BRCA carriers to different arms of trials is an
extremely difficult and rather impossible process given the current available evidence.

Breast Cancer Outcome Similar With and Without BRCA1

NEW YORK (Reuters Health) Feb 08 - In women with triple-negative breast cancer, carriage of the BRCA1
mutation is not an independent predictor of survival, researchers report in a January 24th online paper in
Cancer.
As Dr. Nadine Tung told Reuters Health by email, "Our study found that women who were BRCA1 mutation
carriers had a similar prognosis to women who were not carriers following a diagnosis of triple-negative breast
cancer."
"These findings have implications for patients and their physicians when discussing treatment recommendations
such as chemotherapy and preventive surgeries such as mastectomy," she added.
Dr. Tung of Beth Israel Deaconess Medical Center, Boston, and colleagues note that triple-negative breast
cancer accounts for the majority of breast cancers that develop in women with germline mutations in the
BRCA1 breast cancer susceptibility gene.
To gauge the impact of the mutation, the researchers examined data on 46 BRCA1 carriers and 71 noncarriers,
all of whom received alkylating chemotherapy.
Median follow-up was for more than 6 years. Freedom from distant metastasis at 5 years was 76% for carriers
and 70% for noncarriers. Sites didn't differ significantly but carriers had a propensity for brain relapse (58%
versus 24%).
Overall survival at 5 years was 82% for carriers and 74% for noncarriers. However, after adjustment for age and
stage, mutation status didn't independently predict freedom from distant metastasis, breast cancer-specific and
overall survival.
"Although mutation carriers did not have improved survival rates with conventional chemotherapy as shown in
this study, promising new therapies such as PARP inhibitors and platinum agents are being actively investigated
for women with triple-negative breast cancer," concluded Dr. Tung.
Cancer. Posted online January 24, 2011. Abstract

Some BRCA1 Carriers Less Sensitive to Taxane

NEW YORK (Reuters Health) Aug 12 - Taxanes are less effective in some patients with BRCA1 mutations,
according to Dutch investigators.
If confirmed, the results "can have a major impact on the choice of type of (adjuvant) chemotherapy in BRCA1
mutation carriers with hormone receptor negative or triple negative breast cancer," said lead author Dr. Mieke
Kriege in email to Reuters Health.
In a July 14th online paper in Cancer, Dr. Kriege and colleagues at Erasmus MC-Daniel den Hoed Cancer
Center in Rotterdam note there is growing evidence from preclinical studies that sensitivity to taxanes requires a
functional BRCA1 protein.
The present study, they write, "confirms the preclinical data, however, only for BRCA1-associated patients with
hormone receptor (HRec)-negative and not HRec-positive breast cancer."
The researchers studied 48 patients who had received either docetaxel (Taxotere) or paclitaxel (Taxol) for
metastatic breast cancer, including 35 BRCA1 carriers and 13 BRCA2 carriers. They also analyzed 95 matched
controls with sporadic metastatic breast cancer.
Compared to the control group, the BRCA1 carriers had fewer objective responses (23% vs. 38%), more
progressive disease (60% vs. 19%) and a shorter median progression-free survival (2.2 vs. 4.9 months).
In the subgroup of HRec-negative patients, objective response rates were 20% in BRCA1 patients and 42% in
patients with sporadic disease. Seventy percent of HRec-negative BRCA carriers had disease progression, vs.
26% of controls. The mutation carriers also had a shorter progression-free survival: 1.8 vs. 3.8 months.
In the HRec-positive patients, however, outcomes were similar in BRCA1 carriers and controls.
In BRCA2-associated patients, who were mainly HRec-positive, the objective response was higher than in
sporadic patients (89% vs. 38%).
If the results can be replicated, Dr. Kriege said, HRec-negative BRCA carriers might be better off with an
anthracycline- or platinum-containing regimen instead of taxane chemotherapy, "which is nowadays a
cornerstone in most of the adjuvant chemotherapeutic regimens."
SOURCE: http://bit.ly/nNb6XK
Cancer 2011.

Reproductive Risk Factors for Breast Cancer Differ With BRCA1 vs BRCA2
January 13, 2014
By Will Boggs MD
NEW YORK (Reuters Health) Jan 10 - The association between reproductive factors and breast cancer risk
differ in women with BRCA1 vs BRCA2 mutations, researchers from China report.
Their conclusions are drawn from a systematic review and meta-analysis of 10 studies including 10,807 cases of
breast cancer and 10,591 controls, all of whom carried mutations in BRCA1 or BRCA2.
There was no significant association between parity and breast cancer risk among either BRCA1 or BRCA2
mutation carriers, according to Dr. Xiaoan Liu from The First Affiliated Hospital with Nanjing Medical
University, Nanjing, China and colleagues.
In contrast, older age at first birth, breastfeeding for at least 1-2 years, and older age at menarche were
associated with a significantly lower breast cancer risk among women with BRCA1 mutations, the authors
wrote in a paper online December 12th in Cancer Epidemiology.
Age at first birth, breastfeeding, and age at menarche did not influence the risk of breast cancer among BRCA2
mutation carriers.
"The results suggest a differential risk of breast cancer among BRCA1 or BRCA2 mutation carriers associated
with reproductive factors," the researchers conclude. "The differential risk seen in BRCA1 and BRCA2
mutation carriers associated with reproductive factors suggests that responses to hormonal influences may be
distinct between them."
"Future studies are needed to explore the mechanisms by which the effects of these reproductive factors on
breast cancer risk differ between BRCA1 and BRCA2 mutation carriers, providing information about what can
be done to reduce breast cancer risk," they add.
Dr. Liu and coauthor Dr. Wenbin Zhou did not respond to a request for comments.
In email to Reuters Health, Dr. Leena Hilakivi-Clarke from Georgetown University, Washington, DC pointed
out, "Determining whether reproductive factors modify the risk of breast cancer in women who have a high risk
of getting breast cancer due to a germline mutation in 'powerful' tumor suppressor genes is of importance,
because they can impact a woman's decisions whether and when to have mastectomy and salpingo-
oophorectomy,"
"Findings indicate that late pregnancy protects against breast cancer, compared to early pregnancy, which is
totally opposite to the effect of pregnancy on sporadic breast cancer," Dr. Hilakivi-Clarke explained.
"It is not really discussed why this is," she continued. "One possibility is that early first pregnancy increases the
risk significantly, compared with protective effects seen in non-mutation carriers, and therefore the increase in
risk within mutation carriers is seen in women older than 30 who still might have higher risk than nulliparous
women but not as high as mutation carriers who have a child at a young age."
"Results could be interpreted to suggest that BRCA1 mutation carriers should wait until they are 30 to have
their first child and then nurse for a long time, perhaps up to two years," Dr. Hilakivi-Clarke said. "BRCA2
mutation carriers do not need to worry that reproductive factors modify their risk of developing breast cancer."
But Dr. Claudine Isaacs from Georgetown University told Reuters Health by email that she would be "very
careful" about using these results to counsel BRCA1 and BRCA2 carriers. "These findings were based on meta-
analyses from retrospective studies and while interesting are not of sufficient power for us to make management
recommendations," she said.
"I agree with Dr. Hilakivi-Clarke that it is somewhat surprising that reproductive risk factors do not impact
BRCA2 carriers, who tend to develop tumors more similar to those seen in women with sporadic disease (and
are more often ER+)," Dr. Isaacs said.
"We are learning more about how established reproductive risk factors relate to various molecular subtypes of
breast cancer (in this case, the tumors that BRCA1 and 2 carriers tend to develop)," Dr. Rebecca Troisi from the
National Cancer Institute in Bethesda, Maryland told Reuters Health.
"BRCA1/2 carriers are unlikely to change their reproductive behaviors based on these results, but the findings
may provide some insight into the biological mechanisms of tumorigenesis related to these particular molecular
subtypes," Dr. Troisi said.
SOURCE: http://bit.ly/1ktIwc0
Cancer Epidemiol 2013.

Nature Reviews Cancer 12, 68-78 (January 2012) | doi:10.1038/nrc3181

Article series: Genomic instability in cancer
Opinion: BRCA1 and BRCA2: different roles in a common pathway of genome protection
Rohini Roy1, Jarin Chun1 & Simon N. Powell1 About the authors
The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a
common pathway of genome protection. However, the two proteins work at different stages in the DNA damage
response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint
activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous
recombination. The links between the two proteins are not well understood, but they must exist to explain the
marked similarity of human cancer susceptibility that arises with germline mutations in these genes. As
discussed here, the proteins work in concert to protect the genome from double-strand DNA damage during
DNA replication.

Counsel Women With Likely BRCA Family History: Panel

Apr 02, 2013 By Genevra Pittman
NEW YORK (Reuters Health) Apr 02 - Doctors should screen women for a family history of breast or ovarian
cancer to see if the cancers might be due to certain mutations - and if so, women should be counseled about
their personal risks before getting tested, a government-backed panel said this week.
One in 300 to one in 500 women has a BRCA mutation. According to the National Cancer Institute, a woman's
chance of getting breast cancer during her lifetime increases from 12% to 60% if she carries the mutation, and
ovarian cancer from 1.4% to between 15% and 40%.
The new guidelines, from the U.S. Preventive Services Task Force, are in draft form and will be available for
public comment through April 29 here: http://bit.ly/aF5NPd.
The panel said there is no benefit - and potential harm - in testing women for mutations if they have no family
history of cancer or if their family history doesn't suggest an underlying genetic cause.
"The message for most people is, 'This test is not going to benefit you in any way,'" said Dr. Virginia Moyer,
chair of the USPSTF and a professor at Baylor College of Medicine in Houston.
"But for women who do have a family history, it's clear there is a benefit if you winnow it down to the right
people," she told Reuters Health.
To determine if a family history of cancer is likely tied to BRCA mutations, doctors use a standardized
questionnaire that addresses the number of relatives a woman has with cancer and the age at which they were
diagnosed, among other factors.
If women are referred for genetic counseling, they still have to decide whether or not to be tested. That's not an
easy choice, Dr. Moyer said, because test results aren't always clear cut.
"Part of the problem is an awful lot of the time what you find out is nothing," she said. "You find out, 'Well,
maybe.' And that's a very uncomfortable place to be."
Women who are found to carry BRCA mutations have a number of options to reduce their risk of breast or
ovarian cancer, but most haven't been well studied - and each can cause side effects or complications. For
example, they can undergo frequent screening, take estrogen-blocking drugs such as tamoxifen, or have their
breasts and ovaries removed.
The panel did not make a recommendation about which of those options is best, concluding that more research
is needed to determine the benefits and potential harms of each intervention.
"The options right now for things that we know are going to be effective are pretty extreme," Dr. Moyer said.
Her group's draft guidelines are based on an analysis of past studies suggesting genetic counseling may ease
anxiety and depression among women and improve how accurately they interpret their own cancer risks.
They echo the panel's recommendations on BRCA counseling and testing from 2005.
Ellen Matloff, director of cancer genetic counseling at the Yale Cancer Center in New Haven, Connecticut, said
she hopes future recommendations will cover counseling for BRCA mutations in men - who are also at risk of
mutation-related cancers or passing the mutations on to their children.
"It's really important that we once and for all eliminate the notion that only women carry these mutations," she
said.
Genetic counseling could also be important for people with a newly-diagnosed cancer who are trying to make
treatment choices, or for cancer survivors who may be prone to future disease, Matloff added.
Among people at risk for carrying a mutation linked to cancer, she agreed with the USPSTF that an in-depth
family history and risk assessment should be done before offering genetic testing.
"It's a pretty detailed conversation," Matloff, who wasn't involved in the new guidelines, told Reuters Health.
SOURCE: http://bit.ly/aF5NPd USPSTF 2013.

Impact of Risk-Reducing Strategies in BRCA Mutation Carriers Outlined

January 28, 2009 – Women who find that they are carriers of BRCA mutations, and therefore at a significantly increased risk of developing
breast and ovarian cancer, have a variety of options that they can pursue to reduce that risk.
But choosing which option to pursue can be daunting task, especially because some can appear rather drastic, such as surgery in still-healthy
women to remove the ovaries and/or breasts.
Advising women on which option to choose is a difficult task because there are no data from randomized trials that compare the various
approaches, and it is unlikely that such trials will ever be carried out.
However, there are data on each strategy alone, and by combining all of these data, a group of researchers has come up with a computer-
simulation model that quantifies the impact of each decision.
"Our analysis aims to enhance patient care by bridging the evidence gap," say the researchers, Allison Kurian, MD, and colleagues, from
Stanford University School of Medicine in California. "We provide a computer model that integrates the best available data."
Details are outlined in a paper published in the January 10 issue of the Journal of Clinical Oncology.
This decision analysis will prove to be an important reference for physicians.
"This decision analysis will prove to be an important reference for physicians, other genetic professionals, and most importantly, patients with
BRCA mutations," according to an accompanying editorial.
"The results of this study have the potential to markedly facilitate decision making," write the editorialists, Zsofia Stadler, MD, and Noah
Kauff, MD, both from the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City.
Decision-Analysis Model
The computer-simulation model integrates empiric data from the literature to estimate the survival probability for women with BRCA1 and
BRCA2 mutations.
The model simulates the life histories of a 1980 birth cohort of 1 million women with BRCA1 or BRCA2 mutations from the ages of 25 to 100
or death, whichever comes first, the researchers explain. The key findings are outlined below.
Women With BRCA1 Mutation
Women who carry the BRCA1 mutation have a 53% chance of reaching the age of 70, as does 84% of the general population in the United
States. They have an equal chance of dying from breast or ovarian cancer (41% vs 36%, conditional on death by age 70).
The most effective combination strategy is a prophylactic mastectomy at age 25 plus a prophylactic oophorectomy at age 40; together, this
strategy increases the chance of reaching the age of 70 to 79%. This represents a survival gain of 26% by age 70, compared with no
intervention (79% vs 53%).
Postponing the mastectomy until age 40, but in the meantime undergoing breast screening, and having an oophorectomy at age 40 reduces
this survival gain only slightly (by 2%), to 24%. Similarly, opting not to have a mastectomy and instead undergoing breast screening from the
ages of 25 to 69 and having an oophorectomy at age 40 also reduces the survival gain only slightly (by 3%), to 23%.
The most effective single intervention is an oophorectomy at age 40, which increases the chance of reaching the age of 70 to 68%, and
represents a 15% absolute gain over no intervention (68% vs 53%).
Delaying the oophorectomy until age 50 cuts this absolute gain by half (8% vs 15% at age 40).
Opting for mastectomy alone at age 25 reduces the absolute gain slightly (by 2%), and yields a 13% absolute gain, compared with no
intervention. Delaying the mastectomy until age 40 reduces it even further (by 4%), to an 11% absolute gain.
Opting for breast screening alone from the ages of 25 to 69 yields the lowest absolute gain (6%) of the single-intervention options.

Women With BRCA2 Mutation

Women with the BRCA2 mutation have a 71% chance of reaching the age of 70, as does 84% of the general population in the United States.
These women have a greater chance of dying from breast than from ovarian cancer (36% vs 20%, conditional on death by age 70), but
noncancer deaths are more frequent (44%) than deaths from either cancer among these women.
The most effective combination strategy is mastectomy at age 25 plus oophorectomy at age 40, which together provide a 12% survival gain
by age 70, compared with no intervention (83% vs 71%).
Postponing mastectomy until age 40, but in the meantime undergoing breast screening, and having an oophorectomy at age 40 reduces the
survival gain slightly (by 1%), to 11%. Similarly, opting not to have a mastectomy but instead to undergo breast screening from the ages of
25 to 69 and having an oophorectomy at age 40 reduces the survival gain slightly (2%), to 10%.
The most effective single strategy is mastectomy at age 25, yielding a 8% gain, compared with no intervention (79% vs 71%).
Postponing mastectomy until age 40 reduces this only slightly (by 1%), to a 7% absolute gain.
Opting for an oophorectomy at age 40 yields a 6% survival gain, relative to no intervention (77% vs 71%). Delaying oophorectomy until age
50 reduces this slightly (by 2%), to a 4% gain.
Breast screening alone, with annual magnetic resonance imaging and mammography, provides a 4% absolute gain.
Better-Informed Choices
The authors hope that their computer model will "facilitate shared decision making, guiding women with BRCA1/2 mutations toward better-
informed choices between prophylactic surgery and screening alternatives."
"Individual women make widely disparate choices about how to manage their cancer risks, depending on their family history, healthcare
access, reproductive concerns, and concurrent diagnoses," Dr. Kurian and colleagues explain.
Our results can anchor such choices quantitatively.
"Our results can anchor such choices quantitatively, helping a woman weigh strategies that yield small differences in survival, yet potentially
larger differences in physical and emotional effects, according to her preferences," they add.
Both the researchers and the editorialists point out limitations to the model, and note that there are many questions that have not been
addressed, which could alter judgments about the efficacy and tolerability of the different strategies. For example, one issue is the affect of
menopausal hormone therapy in women who opt to have an oophorectomy at an early age, and another is the impact of partial rather than
complete mastectomies.
"Future updates will be needed," the editorialists write.
The study authors have disclosed no relevant financial relationships. Editorialist Dr. Kauff reports having served as a consultant and having
provided expert testimony for Wyeth.
J Clin Oncol. 2010;28:222-231. Abstract

BRCA1-deficient mammary tumors are highly sensitive to PARP inhibitor AZD2281 05.02.09
A genetically engineered mouse model of cancer can be used for preclinical evaluation and novel therapeutics
and to test ways to overcome or circumvent therapy resistance
Poly(ADP-ribose) polymerase 1 (PARP1) is involved in the surveillance and maintenance of genome integrity,
and functions as a key molecule in the repair of DNA single-strand breaks (SSBs). Inactivation of SSB repair by
PARP1 inhibition during S-phase induces DNA double-strand breaks (DSBs) and may thus confer synthetic
lethality to cells that have defective homology-directed DSB repair. BRCA-deficient cells appear to be highly
sensitive to PARP inhibition, resulting in increased genomic instability, cell cycle arrest, and apoptosis.
A group of authors led by Sven Rottenberg from The Netherlands Cancer Institute, Amsterdam, The
Netherlands, reported in the November 2008 issue of the Proceedings of the National Academy of Science of
the USA on a study that tested the PARP inhibitor AZD2281 in genetically engineered K14cre;Brca1f/f,p53f/f
mouse model for hereditary breast cancer. The Brca1-/-;p53-/- mammary adenocarcinomas arising in this model
recapitulate several key features of human BRCA1-associated breast cancer, including a basal-like phenotype,
lack of ER-, PR-, and ERBB2-expression, and a high degree of genomic instability. They may therefore be a
good predictor for clinical responses of BRCA1-deficient cancers to AZD2281.
Treatment of tumor-bearing mice with AZD2281 inhibited tumor growth without signs of toxicity, resulting in
strongly increased survival (a 100-day schedule increased median survival after the start of treatment from 10
days to 131 days). Long-term treatment with AZD2281 in this model resulted in the development of drug
resistance, caused by up regulation of Abcb1a/b genes encoding P-glycoprotein efflux pumps. This resistance to
AZD2281 could be reversed by coadministration of the P-glycoprotein inhibitor tariquidar. The authors also
evaluated combining AZD2281 with cisplatin or carboplatin. Combination treatment resulted in increased
recurrence-free and overall survival, suggesting that AZD2281 increases the effect of these DNA-damaging
agents.
The authors illustrated in this research that genetically engineered mouse models could be valuable in
optimizing the combination of PARP1 inhibitors with other drugs for investigation in further clinical trials.
The work was supported by grants from the Dutch Cancer Society, The Netherlands Organization for Scientific
Research, and the European Union FP6 Integrated Project, and by fellowships from the Swiss National Science
Foundation and the Swiss Foundation for Grants in Biology and Medicine.

BRCA2 Breast Cancer More Sensitive to Chemotherapy

NEW YORK (Reuters Health) Jul 17 - Compared with patients with sporadic breast cancer, those with BRCA2-associated cancer are more
sensitive to standard first-line chemotherapy for metastatic disease, Dutch researchers report in the June 29th issue of the Journal of Clinical
Oncology.
Dr. Mieke Kriege of the Rotterdam Family Cancer Clinic and colleagues note that a number of preclinical and other studies have suggested
that breast cancer cells without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents.
To examine whether this might have any clinical impact, the researchers retrospectively studied data on 93 patients with BRCA1- and 28 with
BRCA2-associated breast cancer. All were treated with chemotherapy for metastatic disease before January 1, 2007. The most frequently
used chemotherapy regimens used were anthracycline-based and cyclophosphamide, methotrexate, and fluorouracil.
Patient outcomes were compared with those of matched patients with sporadic disease. The BRCA2 patients had a median progression-free
survival of 11.4 months, significantly longer than the 6.7 months seen in the sporadic group. BRCA1 patients had slightly greater median
survival (7.6 months), but this did not reach significance.
The rates of overall survival were similar, with a median of 19.3 months in BRCA2 patients, 13.6 months in sporadic patients and 15.0
months in BRCA-1 patients.
"We observed a significantly increased chemosensitivity to first-line standard chemotherapy for metastatic breast cancer in BRCA2-mutation
carriers as compared to sporadic patients accompanied by a significantly increased overall survival," the researchers conclude.
"For BRCA1-mutation carriers," they add, there was a trend towards a better response rate and clinical benefit as well as "longer progression-
free survival."
In comments to Reuters Heath, Dr. Kriege added that "the observation of the high efficacy of anthracycline-based regimens is especially
reassuring. However, larger additional studies are urgently needed to investigate further newer combination regimens...to make firm
conclusions about the efficacy of different treatment regimens in BRCA1/2 mutation carriers."
J Clin Oncol 2009;27.
Simultaneous Operations Feasible for Hereditary Breast-Ovarian Cancer
Syndrome
NEW YORK (Reuters Health) Apr 23 - As a cancer prevention strategy for BRCA1/2 mutation
carriers, prophylactic mastectomy and bilateral salpingo-oophorectomy can be combined into a single
operation with acceptable morbidity, the results of a small retrospective study suggest.
On average, the combined procedure took 9.3 hours to perform and patients were hospitalized for 5.4
days afterward, according to the report in the April 14th online issue of BMC Cancer.
Carriage of BRCA1 or BRCA2 mutations is known to greatly increase the risk of both breast and
ovarian cancer, lead author Larissa I. Batista and colleagues state. By 70 years of age, 40% to 85% of
carriers will develop invasive breast cancer and 15% to 65% will develop invasive ovarian cancer.
The management of women with these mutations, the team from the University of Texas M. D.
Anderson Cancer Center in Houston notes, can involve intense clinical follow-up, chemoprevention
with tamoxifen, or prophylactic mastectomy and bilateral salpingo-oophorectomy. Although the last
approach is more aggressive, research has shown it to be highly effective in preventing the associated
malignancies.
Typically, the mastectomy is performed first and the bilateral salpingo-oophorectomy is performed
months later during one of the breast reconstructive procedures that most patients elect to undergo.
Whether the mastectomy and bilateral salpingo-oophorectomy could be safely combined into one
procedure was unclear.
The new findings, which are based on a review of 12 patients treated at the authors' center, suggest that
prophylactic mastectomy and bilateral salpingo-oophorectomy can be rolled into one operation without
undue risk to the patient. The average patient age was 43 years and 10 of the women had a prior breast
cancer. Ten women also underwent bilateral breast reconstruction during the combined procedure.
None of the patients experienced any major complications during the operation. Afterward, however,
one patient each developed an abdominal wound dehiscence, flap congestion requiring reoperation,
umbilical superficial epidermolysis, and aspiration pneumonia.
Ten patients remained cancer-free at mean follow-up period of 84 months, the results indicate. None of
the patients developed a new primary cancer, but two patients developed a distant recurrence.
According to the authors, enhanced patient convenience is a key advantage with the combined
procedure. In addition, performing oophorectomy at the time of mastectomy allows for "the initiation
of aromatase inhibitors for endocrine treatment in premenopausal patients with estrogen-receptor
positive disease." Lastly, doing both procedures at once reduces the theoretical risk that ovarian cancer
will arise between staged procedures.
BMC Cancer 2008;8.

Prophylactic Mastectomy in Women With BRCA Gene Mutations

Reduces Risk for Breast Cancer to Less Than 1%
April 16, 2008 — Women who carry the BRCA gene mutation have an estimated 85% lifetime risk of
developing breast cancer, but a prophylactic mastectomy reduces this risk to less than 1%, Dutch
researchers told the 6th European Breast Cancer Conference in Berlin, Germany, today.
Previously, it was thought that the risk was reduced to about 5%, commented lead author Reinie Kaas,
MD, from the surgical department of the Netherlands Cancer Institute, in Amsterdam. As a result, there
has been some debate about whether women undergoing prophylactic mastectomies should continue
with surveillance or not, she explained. She said that the latest results compiled by her team show that
continued surveillance is not, in fact, necessary.
Dr. Kaas and colleagues reported a series of 251 women who underwent a uni- or bilateral mastectomy
after 1 or more rounds of surveillance. The standard procedure was skin-sparing mastectomy with
immediate reconstruction with an implant. About two thirds of these women had the BRCA1 gene
mutation (n = 179), and the remainder had the BRCA2 gene mutation (n = 72).
Only 1 of the 251 carriers (0.4%) went on to develop breast cancer, which grew in the incompletely
removed axillary tail (part of the breast that extends under the armpit) 2 years after the prophylactic
mastectomy. This patient is free of disease 6 years after treatment, the researchers reported.
"Our epidemiologists are investigating how many breast cancers are avoided up to the age of 80 in
these women," Dr. Kaas said in a statement. "But on current evidence, we can safely state that
continued follow-up, which can be costly and stressful for the patient, is not warranted in patients who
have had prophylactic mastectomy."
However, the decision to remove healthy breasts must be made solely by the woman, Dr. Kaas
emphasized, and "healthcare services should not press women to make this choice simply to reduce
costs."
Currently, about half the women who carry the BRCA gene mutation opt for this measure, she
commented. The alternative is ongoing surveillance, which involves monthly breast self-examination,
biannual clinical breast examination by a physician, and annual mammography plus breast magnetic
resonance imagining (MRI). However, because BRCA carriers are prone to developing fast-growing
tumors, even with this surveillance, about 25% to 30% of carriers are diagnosed when the tumor is
already more than 2 cm in diameter, she noted.
Intensive Screening is Expensive
The cost of such intensive screening is substantial. Another group of Dutch researchers estimated that
screening of such women costs €254 per woman per year, with an extra cost for further investigations
of around €61 per woman per year.
Part of the expense comes from the use of MRI, commented Yvonne Kamm, MD, medical oncologist at
the Radboud University Nijmegen Medical Center in the Netherlands. "The MRI is expensive in itself,
but useful because it can detect very small tumors that might not be picked up otherwise," she said. "It
also detects many other abnormalities that are not cancer, and this implies not just extra cost but also
considerable anxiety for the women concerned."
In a poster presentation, Dr. Kamm and colleagues outlined the results for 196 women with BRCA gene
mutations who had been screened between 1999 and 2005. The women were screened for a median
period of 2 years, and in total underwent 1149 breast examinations (of which 2% were abnormal), 494
mammograms (9% abnormal), and 436 MRI scans (14% abnormal). When any abnormality was found,
the women underwent further investigation, which led to another 32 breast examinations, 17
mammograms, 64 MRI scans, 114 ultrasound examinations, and 48 biopsies.
During the 6-year period, 13 cancers were found, 11 of which were invasive and 2 of which were in
situ ductal carcinoma. "The total costs to find 1 breast cancer were high — €13,168," Dr. Kamm
commented.
6th European Breast Cancer Conference (EBCC): Abstracts 18 and 109. Presented April 16, 2008.

Combined Breast Screening Provides Best Survival for BRCA1

Mutation Carriers
NEW YORK (Reuters Health) Feb 26 - Among women with BRCA1 gene mutations, annual screening
with both mammography and MRI is associated with better survival than with either screening
modality alone, new research indicates. The downside, however, is a high rate of false-positive results
and biopsies for benign disease.
The findings, reported in Radiology for March, are based on a Markov Monte Carlo decision analysis
using data from the Surveillance Epidemiology and End Results database (1975-1980).
"For women who carry BRCA1 gene mutations, adding annual MRI to annual mammography has a
clear benefit in terms of projected life expectancy and breast cancer mortality reduction," lead author
Dr. Janie M. Lee told Reuters Health. "Whether the trade-offs related to MRI screening are acceptable
to women at increased risk of developing breast cancer is still being investigated."
According to the report, mammography is not nearly as sensitive at detecting breast cancers in BRCA1
mutation carriers as it is in the general population. Previous research has shown that MRI can achieve
higher sensitivity than mammography, but whether this translates into reduced breast cancer mortality
is unclear.
Due to the long length of follow-up and the large number of patients required, the authors note that it is
unlikely that any trial will ever investigate whether MRI screening can reduce breast cancer mortality.
This led Dr. Lee, from Massachusetts General Hospital in Boston, and colleagues to conduct a decision
analysis in a model incorporating 500,000 25-year-old women who were asymptomatic BRCA1
mutation carriers.
The average life expectancy was 71.15 years, the report indicates, and with clinical surveillance alone,
the median diameter of identified breast cancers was 2.6 cm. With annual screening with
mammography, MRI, or both, the median diameters fell to 1.9, 1.3, and 1.1 cm, respectively.
Compared with clinical surveillance, the corresponding increases in life expectancy with the three
imaging-based screening strategies were 0.80, 1.10 and 1.38 years, respectively.
False positive rates, however, were 53.8% with mammography, 80.2% with MRI, and 84.0% with both
modalities, and corresponding rates of biopsies for benign disease were 11.3%, 26.3% and 30.3%.
"Further research is needed to establish the optimal sequence and frequency of MRI and
mammographic screening, and to minimize the potentially negative effects on women's health-related
quality of life when screening with increased intensity is pursued," Dr. Lee noted.
She added that her team is "currently working to extend our model of breast cancer natural history and
screening in BRCA1 gene mutation carriers to women who carry BRCA2 mutations, and women
whose lifetime risk of breast cancer exceeds 20%, as these are women defined by the American Cancer
Society as being at 'high-risk' of developing breast cancer."
Radiology 2008;246:763-771.

Methods for Evaluating Unclassified Variants of BRCA1/2 Yield

Similar Results
NEW YORK (Reuters Health) Mar 25 - Several methods for evaluating unclassified variants in the
breast cancer susceptibility genes BRCA1 and BRCA2 yield similar results, but they are not helpful in
predicting individual risk, according to a report in the BMC journal Breast Cancer Research online
February 19th.
"When encountering a patient with an unclassified variant in BRCA1/2 genes, several methods can
help to broadly categorize the unclassified variants," Dr. Giske Ursin from USC/Norris Comprehensive
Cancer Center, Los Angeles, California told Reuters Health. "However, these methods cannot definitely
predict whether a specific variant will be deleterious or not at this stage."
Dr. Ursin and associates sequenced BRCA1/2 genes in 1469 breast cancer patients and identified 262
distinct variants, including 147 unclassified variants (UVs).
The team classified BRCA1/2 UVs using several methods and then evaluated the validity and
usefulness of each method by comparing the risk categories of UV carriers with respect to well-defined
characteristics of carriers of known deleterious mutations in BRCA1/2.
BRCA1 UV carriers (but not high-risk BRCA2 UV carriers) who were classified as high risk by each
method were more likely than low-risk UV carriers to be similar to carriers of deleterious mutations.
For example, they were more likely to have a first-degree family history of breast or ovarian cancer, the
authors report.
"Our results suggest that several classification methods could be used to get some idea about the
clinical significance of such variants," Dr. Ursin said. "However, these methods, by themselves, cannot
definitely predict whether a specific variant will be deleterious or not. Polyphen may be slightly better
than the other methods, but this will need to be confirmed in another study."
"The following questions need to be addressed (either by us or others) in an independent larger study,"
Dr. Ursin explained. "(1) Whether application of more stringent cut points for several classification
methods improves identification of truly deleterious unclassified variants, (2) whether application of all
methods jointly improves identification of truly deleterious unclassified variants, and (3) whether
unclassified variants predicted to be deleterious in our paper segregate with disease within families."
Breast Cancer Res 2008;10.

Breast Cancer Risk Associated With BRCA1 and BRCA2 in

Diverse Populations
James D. Fackenthal; Olufunmilayo I. Olopade Nat Rev Cancer. 2007;7(12):937-948.
Abstract
Germline mutations in the BRCA1 or BRCA2 tumour-suppressor genes are strong predictors of breast and/or
ovarian cancer development. The contribution of these mutations to breast cancer risk within any specific
population is a function of both their prevalence and their penetrance. Mutation prevalence varies among ethnic
groups and may be influenced by founder mutations. Penetrance can be influenced by mutation-specific
phenotypes and the potential modifying effects of the patient's own genetic and environmental background.
Although estimates of both mutation prevalence and mutation penetrance rates are inconsistent and occasionally
controversial, understanding them is crucial for providing accurate risk information to each patient.
Introduction
Numerous epidemiological factors affect the likelihood of developing breast and ovarian cancer, but no other
predictor is as powerful as an inherited mutation in the tumour-suppressor genes BRCA1 or BRCA2. Even
though hereditary breast cancer accounts for only 5-10% of all breast cancer cases, individuals carrying
mutations in one of these genes have a 40-80% chance of developing breast cancer, making these mutations the
strongest breast cancer predictors known.[1-3]
BRCA1 and BRCA2 were molecularly identified in 1994 and 1995, respectively, and since then patients with
strong personal and/or family history of breast and/or ovarian cancer have been counselled to seek molecular
genetic testing for germline mutations in these genes.[4,5] In the context of this Review, the term 'mutation' will
be used to refer to a disease and/or risk-associated deleterious genetic lesion. Indicators of inherited breast
and/or ovarian cancer syndromes include early age of cancer onset, multiple affected individuals within a family
(especially multiple first-degree relatives), the development of bilateral disease and males with breast cancer. It
has been estimated that 0.7-29% of such families are accounted for by mutations in BRCA1, and 1.5-25% are
accounted for by mutations in BRCA2 (Refs 6-9). Although these reports represent a wide range of population
proportions, most evidence suggests that, in general, germline mutations in known breast cancer risk genes
account for ~20% of breast cancers associated with family history[10,11] (previously reviewed by Szabo and
King[12]). It is therefore crucial to understand the contribution of BRCA1 and BRCA2 mutation-associated risks
to these breast cancer populations.
Studies of BRCA1 and BRCA2 mutation frequencies have revealed great differences in populations from
different geographic regions and ethnicities. For example, 34% of Swedish high-risk families carry deleterious
BRCA1 mutations, and 69% of these are a single mutation. However, only 2% carried mutations in BRCA2 (Ref.
13). By contrast, 32% of similarly high-risk Sardinian families carry one of two common BRCA2 mutations,
and 11% carry a single BRCA1 mutation.[14] In Poland, 64% of high-risk families carry a BRCA1 mutation (one
of nine recurring mutations), but rarely any BRCA2 mutations[15] (similar ranges are reviewed by Szabo and
King[12]). As we approach the goal of personalized medicine, it is important to recognize the contribution of an
individual patient's genotype to her (or his) breast cancer risk, as well as the gene-gene and gene-environment
relationships that may modify mutation penetrance in each individual.
Mutation Prediction and Detection
Patients seeking genetic counselling for breast and/or ovarian cancer risk will be assessed for the likelihood of
carrying a BRCA1 or BRCA2 mutation. Knowing the frequency and range of mutations in a given population
can therefore be an important factor in deciding whether to seek genetic testing.
Patients seeking BRCA1 or BRCA2 genetic testing in a clinical setting will be tested by complete sequencing of
coding regions in most cases (see "Sidebar: Mutation Screening in Patients"); however, the basic and
translational research literature reports a variety of different mutation detection methods, each with its own
strengths and weaknesses. As a result, there are significant inconsistencies between studies. Most detection
strategies begin with a rapid determination of which exons or exon fragments carry sequence variations, then
only those fragments are sequenced. Most of these methods identify PCR fragments with variant base sequences
or heteroduplex denaturation-renaturation products resulting from mismatched strands at points of
heterozygosity. Because most BRCA1 and BRCA2 mutations are protein truncating, many investigators have
used a protein truncation test (PTT) to identify truncated in vitro transcription and/or translation products from
patient complementary DNAs or large exons from genomic DNA. The sensitivities and specificities of the
various detection methods have been reviewed and compared elsewhere.[16,17]
According to the Breast Cancer Information Core (BIC; version modified 31 January 2007), the deleterious
mutations clinically identified in BRCA1 and BRCA2 so far include a small number of missense mutations and a
much larger number of protein-truncating mutations.
Missense Mutations
There have been 27 BRCA1 missense mutations reported, affecting 15 codons (Figure 1). These lie primarily in
regions encoding the BRCA1 protein RING and BRCT domains, which are known to be involved in
functionally important protein-protein interactions. Ten missense mutations affecting eight codons have been
reported for BRCA2. Four mutations in the first codon of BRCA1 (M1I, M1R, M1T and M1V) and three in the
first codon of BRCA2 (M1R, G-to-T M1I and G-to-A M1I) are included with the list of known missense
mutations, but the effects of the base changes in the first codon are more likely to be related to translation
initiation than amino-acid substitution per se. Additionally, several missense mutations are categorized as such
by their predicted amino-acid substitutions, yet the base changes may have more to do with splicing defects
because of their proximity to intron-exon junctions.
Figure 1.
Position of several founder mutations within BRCA1 (top) and BRCA2 (bottom). Exons are indicated by shaded
boxes. Exon numbers are shown beneath. Note that BRCA1 has no exon 4, owing to a correction made after the
initial description. The open-reading frames are indicated by ATG in exon 2 of both genes, and the termination
codons by TGA (BRCA1) and TAA (BRCA2). Positions of founder mutations described in Table 3 are indicated
above.

Truncating Mutations
These include nonsense mutations, frame-shift mutations due to small insertion and/or deletion events, and
mutations within splice sites. Over 670 truncating mutations have been reported for BRCA1, and over 730 for
BRCA2. These mutations occur throughout the lengths of the two genes.[18] In both genes, truncating mutations
are far more frequently observed than deleterious missense mutations.
Larger Genomic Alterations
In addition to point mutations that can be detected within a PCR fragment, BRCA1 and BRCA2 are both known
to have germline mutations resulting from larger-scale genomic rearrangements that result in duplications or
deletions of one or more exons, usually producing premature stop codons. Depending on the selection criteria
and the nationality of the study group, large-scale rearrangements in BRCA1 have been reported as frequently as
2-12% among high-risk families,[19,20] and might represent 7-40% of all BRCA1 mutations identified.[21,22] More
recently, such mutations have been identified in BRCA2 in 2-8% of high-risk families, again varying with the
selection criteria and the population studied.[20,23,24] Such mutations could not be detected by traditional methods,
so their contribution to mutation frequencies in different populations might not always be reported.
Patient Prevalence
Dozens of studies examining 100 or more subjects have been reported, showing the frequency of deleterious
BRCA1 and/or BRCA2 mutations in individuals considered at high risk for carrying mutations by reason of
family history in different ethnic and geographical populations. Nearly the same number of studies have been
performed on cohorts of fewer than 100 subjects. Although the contribution of BRCA1 and BRCA2 mutations to
cancer risk is clearly different in different populations, the true extent of these differences is difficult to gauge
given the wide variety of patient inclusion criteria and mutation ascertainment methods used in different studies.
For example, one study of high-risk patients in the Czech Republic found frequencies of 23.6 % BRCA1 and
11.6% BRCA2 mutation carriers in a large population,[25] whereas an earlier study of Czech patients with similar
inclusion criteria suggested only 2% BRCA1 and 2% BRCA2 mutation carriers.[26] There could be several
explanations for these differences, but one likely possibility is that the more recent study ascertained mutations
using complete sequencing of all BRCA1 and BRCA2 exons and intron-exon boundaries, whereas the earlier
study identified variants using PTT and heteroduplex analysis, then sequenced only potential positives from
these assays. Such pre-screening methods could reduce detection sensitivity. In another example, a study of
high-risk Latina women from the United States showed a 0.7% frequency of BRCA1 mutations,[7] whereas
another study published the same year on another large cohort of high-risk Latina individuals showed a 23%
frequency.[2] Both studies used complete sequencing to identify mutations, but the first study included patients
with two or more affected first-degree relatives (breast or ovarian cancer) with no selection for age of onset,
while the second study used more stringent criteria for high-risk status, including age of disease onset.
Clearly, evaluating the literature describing prevalence of BRCA1 and BRCA2 mutations among high-risk
patients requires an assessment of both cohort selection criteria and also mutation ascertainment methods, but
does one have a greater influence than the other? Obviously the answer could be different in every case, but one
example illustrates the power of limited methodologies to overwhelm other factors. Two studies from two
American cancer risk clinics showed very different frequencies of BRCA2 mutations in cohorts of high-risk
patients. Nanda et al. reported a 25% frequency of BRCA2 mutations in patients from families with two or more
cases of breast and/or ovarian cancer among first- or second-degree relatives,[28] whereas Vaziri et al. reported
only a 1.9% frequency of BRCA2 mutations in patients from families with three or more affected first-degree
relatives, weighted toward early-onset disease and disease occurrence in two or more generations.[29]
Interestingly, the study with the less stringent criteria for at-risk status[28] showed a higher frequency of BRCA2
mutations than the study with the more stringent inclusion criteria. It may be that the different results in these
and numerous other studies are influenced by demographic differences between cohorts that make
reproducibility difficult. However, it is worth noting that Nanda et al. used complete sequencing as the mutation
detection method, whereas the Vaziri et al. study used a combination of pre-selection techniques to limit the
number of exons sequenced directly.
Sporadic Breast Cancer
Mutations in BRCA1 or BRCA2 have become associated with high-risk families, yet it is important to
understand the likelihood of these mutations occurring in individuals who are not from high-risk families. As
breast and ovarian cancer occurring in the same family is a hallmark for BRCA1 and/or BRCA2 mutation
carriers, several investigators have sought to address the frequencies of BRCA1 and BRCA2 mutations in
ovarian cancer patients unselected for family history or age of disease onset. The results suggest BRCA1
mutation frequencies ranging from 4 to 29% and BRCA2 mutation frequencies from 0.6 to 16% ( Table 1 ).
Similarly, several groups have investigated the frequencies of these mutations in early-onset breast cancer cases,
again unselected for family history ( Table 1 ), finding BRCA1 mutation frequencies from 0.7 to 10% and
BRCA2 mutation frequencies from 1 to 6% ( Table 1 ). Interestingly, one analysis of a cohort of breast cancer
cases diagnosed at age 40 years or younger from the Australian Breast Cancer Study showed that roughly 5% of
these early-onset cases carried either a BRCA1 or a BRCA2 mutation.[30] This study confirmed other studies that
showed that the likelihood of finding a mutation in either BRCA1 or BRCA2 increases in line with the number
of affected first-degree relatives. However, this study also showed that most early-onset patients in whom
BRCA1 and BRCA2 mutations were identified had no family history of breast cancer. Thus, although the
frequency of mutations among individuals with strong family history may be greater than the frequency in
patients with no family history, in a clinical setting the proportion of patients with family history may be small
compared with that of patients without family history.[30] The important conclusion for clinicians is that it is
likely most BRCA1 and BRCA2 mutations occurring in a clinical setting will be present in individuals with no
family history of breast cancer.
Finally, the observation that male breast cancer is the single inherited breast cancer susceptibility phenotype not
associated with BRCA1 mutations (the observation that prompted the search for BRCA2), inspired several
studies that examined the frequencies of BRCA2 mutations in male patients with breast cancer unselected for
family history or age of onset, revealing BRCA2 mutation frequencies of 7-14% ( Table 1 ).
The studies listed in Table 1 indicate that identifying the prevalence of BRCA1 and BRCA2 mutations in patients
without strong family histories would be informative. By examining cohorts that retain isolated features of high-
risk families (ovarian cancer, early-onset breast cancer or male breast cancer), these studies begin to address the
relative predictive values of individual high-risk familial phenotypes for identifying BRCA1 and BRCA2
mutations. In general, patients unselected for family history but who nonetheless have ovarian cancer, early-
onset breast cancer or male breast cancer, are more likely than sporadic cases to harbour BRCA1 and BRCA2
mutations. Overall, it is likely that the true frequency of BRCA1 and BRCA2 mutations, with the exception of
high-frequency founder mutations (see below), cannot be shown rigorously to differ between populations, as no
single definition of 'high-risk family' or 'early-onset disease' is equally applicable to all populations, and
penetrance modifiers of mutations (a major influence in the appearance of affected family members) will not be
similar in all genetic and environmental backgrounds. However, understanding the role of BRCA1 and BRCA2
mutations as risk factors in patients with no particular personal or family cancer history is crucial to
understanding breast and ovarian cancer risk factors in general populations, although the low frequency of these
mutations in general populations makes risk difficult to determine with statistical rigour. To overcome these
challenges, several groups have taken advantage of multi-institutional collaborative studies to identify BRCA1
and BRCA2 mutation frequencies in large cohorts of breast and ovarian cancer patients unselected for family
history, age of onset or other indicators of high-risk status ( Table 2 ). As anticipated, the mutation frequencies
in different populations are generally low (0-7% for BRCA1 and 1-3% for BRCA2; Table 2 ).
Thus, some BRCA1 and BRCA2 mutation carriers without family history of disease may have comparatively
low (but still clinically significant) mutation-associated penetrance, whereas others may have uninformative
family structures that do not reveal family history regardless of mutation penetrance, such as small size, few
female relatives or patrilineal inheritance of the mutation. In the future, genetic counsellors advising patients on
whether to seek genetic testing may cooperate with pathologists and molecular biologists to take advantage of
other biological indicators of BRCA1 and BRCA2 mutation status. For example, it has been demonstrated that
the gene expression profiles of sporadic and BRCA1-associated tumours are distinct[31] and the
immunohistopathological profile of BRCA1-associated tumours, phenotypically a subset of basal-like tumours
(having molecular markers that are characteristic of basal epithelial cells; see below), are also distinguishable
from other tumour subtypes.[32,33] Such distinguishing characteristics are already providing the basis for future
predictions of BRCA1 and BRCA2 mutation status. For example, women with 'triple negative' -- ER-, PR- and
HER2- -- breast cancer are candidates for BRCA1 testing, and new genomic technologies are being developed to
make it more practical to carry out large numbers of predictive tests in a clinical setting, as those with a family
history probably represent only a fraction of mutation carriers.
Once a mutation has been identified, patients need to be counselled on their likelihood of developing cancer,
that is, they need to know the penetrance of their mutations in the context of their own genetic and
environmental backgrounds. Although penetrance estimates for BRCA1 and BRCA2 mutations are vital to risk
assessment, they remain highly controversial. Some studies examined penetrance in very high-risk families
(four or more breast cancer cases) with a BRCA1 or BRCA2 mutation carrier proband. Age-specific cumulative
risks by 70 years were typically high in these families, with BRCA1 or BRCA2 mutation carriers having an 80-
87% likelihood of developing breast cancer, and a 27-63% likelihood of developing ovarian cancer.[34-36] One
study showed a lower risk of breast cancer (67%) among BRCA2 mutation carriers in families with four or more
cases of breast or ovarian cancer.[37] A more recent study using families from high-risk counselling clinics with
varying inclusion criteria found even lower penetrance for BRCA1 and BRCA2, with breast cancer risks of 46%
and 43%, respectively, and ovarian cancer risks fell within the broad ranges reported previously, 39% and 22%,
respectively.
To ascertain the true penetrance of BRCA1 and BRCA2 mutations in more general populations, several
laboratories have worked to determine the penetrance of mutations found in large hospital-based cohorts that
have not been selected for family history or ethnicity. As the frequency of BRCA1 and BRCA2 mutations in such
unselected populations is typically so low that it precludes meaningful statistical analysis, some of these studies
used populations selected for age of onset, anywhere between 40 and 55 years of age, in order to enrich for
BRCA1 and BRCA2 mutations.
Results from these studies, again, show risks of breast cancer that are associated with deleterious mutations in
BRCA1 or BRCA2 to be somewhat lower (47-57% and 31-56%, respectively, by the age of 70 years) than the
risks ascertained from studies of high-risk families.[38-40] The ranges of ovarian cancer risks in these studies
narrowed considerably for mutations in BRCA1 and BRCA2 (36-39% and 10-11%, respectively, by the age of
70 years).[38,39] Risch et al. estimated a BRCA1-mutation-associated risk by the age of 80 years of 68% for breast
cancer and 36% for ovarian cancer.[41] Other studies evaluated the cancer risks associated with BRCA1 and
BRCA2 mutations together, finding a 40% risk of breast cancer by the age of 70 years[30] or risks of breast or
ovarian cancer of 73.5% and 27.8%, respectively, by the age of 80 years.[42] Again, these studies show that the
penetrance of deleterious BRCA1 and BRCA2 mutations is lower overall in a general population than in high-
risk families, but the variability is broad and the confidence intervals are wide. Reasons for this variability may
include different cut-off ages used to define early onset in different populations, pedigree-specific genetic
and/or environmental modifiers, or different ethnically-defined genetic mixes in the different populations
studied.
Some of the variability within and between studies may be due to real biological differences between
populations. For example, several studies have shown that the penetrance for some deleterious mutations in
some populations has actually increased several-fold over recent decades, so the ages of the subjects in a given
study could affect the outcome of the penetrance estimates considerably.[39,43,44] Other studies describe the
importance of determining whether subjects within affected families have had prophylactic oophorectomies or
mastectomies. These procedures have been shown to have benefits in BRCA1 and/or BRCA2 mutation carriers
in both reduced cancer risk and prolonged life expectancy,[45-47] and it has been demonstrated that individuals
who test positive for BRCA1 and BRCA2 mutations seek prophylactic surgeries in large numbers.[48,49] This can
have a great effect on risk estimates ascertained through prospective studies.[50,51] Yet information relating to
prophylactic surgeries is not always collected from study populations used to determine penetrance.
Some discrepancies between penetrance estimates in different studies may also be due to differences in
statistical analyses of results. For example, although most agree that BRCA1 and BRCA2 mutation penetrance
may appear higher in carriers from high-risk families using raw data, there are different methods used to make
statistical corrections for these overestimates,[37,51] and there may be different results when reporting relative
versus absolute risks.[39] Differences may also occur when important parameters are estimated rather than
measured directly. For example, most studies use statistical models to estimate the number of mutation carriers
in families with a proband, whereas King et al. (2003) used direct sequencing to determine the mutation status
of members in affected families. Unlike other studies, this study concludes that mutation carriers with no family
history of breast and/or ovarian cancer have as great a cancer risk as those from high-risk families.[44] Likewise,
penetrance estimates may seem different in prospective versus retrospective studies of family members carrying
deleterious BRCA1 and/or BRCA2 mutations.[40]
Different penetrance estimates have also been described for specific BRCA1 and BRCA2 mutations.[52,53] Among
the most extensively described of these different mutation-specific phenotypes are those associated with
mutations that fall within the proposed BRCA2 ovarian cancer cluster region (OCCR) -- a region of ~3.3 kb in
exon 11 in which truncating mutations are associated with a higher incidence of ovarian cancer compared with
breast cancer, relative to truncating mutations in other regions of BRCA2 (Refs 41,54-56). As these are
truncating mutations, it would be expected that the mutant transcripts would be subject to nonsense-mediated
mRNA decay (NMD), resulting in reduced mRNA levels from the mutant allele.[57,58] However, NMD has
varying levels of efficiency, and it is certainly possible that these suggested mutation-specific phenotypes reflect
some amount of mRNA that escapes NMD in the pre-cancerous cells in which these causative mutations exert
their deleterious effects, or that NMD itself is misregulated in cancer cells, affecting the aetiology of tumours in
a BRCA2-mutation-specific manner. Still, the phenotypes reported for the OCCR are not reproducible in all
populations,[59] and NMD has been observed to affect mRNA containing BRCA2-OCCR-truncating mutations.[60]
As yet, no truncated BRCA2 protein has ever been demonstrated to accumulate in cells carrying OCCR
mutations.
Different mutation-specific phenotypes have been ascribed to some BRCA1 mutations but, again, no truncated
proteins have yet been observed. Indeed, NMD has been examined directly in BRCA1 (Ref. 61) using
lymphoblastoid cell lines from affected families. In this regard, perhaps the most informative BRCA1 mutations
are the set of large-scale rearrangements that remove both promoter sequences and the first exon of BRCA1
(Refs 22,62). These mutations may be thought of as true molecular nulls, as they are not transcribed. So far
there has been no observed phenotypic difference between these mutations and many other truncating BRCA1
mutations, providing a phenotypic standard for their null status.
Founder Mutations
One of the most useful ways to approach penetrance estimates is to examine founder mutations, or high
frequency individual alleles that are particular to a specific population. The concept of a founder effect was
described by Ernst Mayr[63] to explain the reduced genetic variability of some small populations relative to their
parent populations. He proposed that, in cases where the small population was founded by a small number of
individuals, they would carry only a small subset of the genetic variability of the parent population. Such a
geographically isolated subpopulation (or parent population that suffers a dramatic decrease or bottleneck)
could then give rise to larger populations with a conspicuous lack of overall genetic diversity, regained as new
variants occur spontaneously or migrate in from other populations.[64,65]
The founder effect has been used to explain the high frequencies of disease-associated mutations in specific
human populations. Classic examples include the high frequencies of the Tay-Sachs mutation in Jewish
populations from eastern Europe (Ashkenazi Jews).[66] It has been estimated that the average individual carries
four recessive-lethal mutations in the heterozygous state,[67] so a founder population of 40 individuals isolated
from a larger parent population would be expected to carry over 100 deleterious mutations.[66] Likewise, a
mutation that immigrated or arose de novo within a small population would be likely to have a higher frequency
among descendants than if it had occurred in a larger population. Such founder mutations would therefore
appear as high-frequency, deleterious mutations in unrelated families from closed populations that exhibit
overall low genetic diversity.
When describing a recurring mutation as a potential founder mutation, it is important to show the mutation
occurred only once in history. There are several examples of recurring mutations in BRCA1 and BRCA2 that
arose multiple times in different populations because their particular local DNA-sequence environments create
mutational hot spots. Such recurring mutations do not represent founder mutations. To make the distinction
between single and multiple historical occurrences of the same mutation, it is necessary to look at genetic
marker variants that are close enough to the mutation to remain associated through numerous generations, with
little or no separation by meiotic recombination. Useful markers include single nucleotide polymorphisms and
microsatellite markers, also known as short tandem repeats. A series of nearby markers that segregate together
as a unit through generations constitutes a haplotype. A recurrent mutation that occurs on a single haplotype in a
population may be considered a founder mutation, while a mutation that occurs on more than one haplotype is
considered to have occurred multiple times in the population history and is not a founder mutation.
Although founder populations in general are especially useful for gene discovery, founder mutations in BRCA1
and BRCA2 have been useful in defining mutation-associated risks in specific populations (see "Sidebar: Using
Founder Mutations to Identify Disease-associated Genes"). Three of the best-characterized BRCA1 and BRCA2
founder mutations are found in Ashkenazi Jewish populations ( Table 3 ). The Ashkenazim are European Jews,
historically separated from other major groups in Africa and the Middle East, though they generally trace their
origins to the Near East before the Roman exile.[68] Ashkenazi Jewish populations have an unusually high
prevalence of more than 20 known recessive disease-associated mutations, and genetic evidence suggests this
reflects a founder effect resulting from a population bottleneck within the last millennium that resulted in a low
number of maternal ancestors.[69,70] The mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT
have been identified in 0.8-1%, 0.1-0.4% and 1-1.5%, respectively, of Ashkenazi Jewish populations.[71,72]
Among Ashkenazi breast cancer cases, these three founder mutations combined account for 6.7-11.7% of all
patients,[73,74] 59% of patients from high-risk breast cancer families,[75] 30% of cases diagnosed under the age of
40 years,[76] and 24-62% of ovarian cancer cases occurring in patients that have not been selected on the basis of
family history.[75-77] Although these three founder mutations are not identified in all high-risk breast and/or
ovarian cancer families, they do represent the majority of germline BRCA1 and BRCA2 mutations found in
Ashkenazi Jewish populations.[78,79] Indeed, one study has found only 16 out of 74 (21%) BRCA1 and BRCA2
mutations identified in an Ashkenazi population were non-founder BRCA1 and BRCA2 mutations.[80]
It is worth noting that BRCA1 185delAG is not found exclusively in Ashkenazi patients. This mutation has been
found in patients of Spanish ancestry as well as other ethnic groups, sometimes with frequencies similar to those
in Ashkenazi populations,[81-83] suggesting that this mutation may have existed before the Jewish diaspora. That
is, because of the history of the Ashkenazi Jews, it is to be expected that this founder mutation may be identified
in populations that do not identify themselves as historically Ashkenazi. That this variant has been found in
patients of Spanish ancestry is probably because many Sephardic Jews were forced to convert to Roman
Catholicism, and it is probably a marker for Jewish ancestry among Spaniards. Additionally, it has been
suggested that microsatellite markers flanking 185delAG are consistent with it having arisen independently in at
least two populations or subpopulations,[83] but these results have not been tested further with higher-resolution
assays.
Another well-studied founder mutation is the Icelandic founder mutation BRCA2 999del5. Genetic evidence, in
accordance with demographic data, suggests the Icelandic population was subject to a greater level of genetic
drift than other European populations, resulting in reduced genetic variation. The founder effect is evident from
the comparatively small number of mitochondrial lineages, mostly originating from Scandinavia and the British
Isles.[84] The BRCA2 999del5 mutation, the sole high-frequency founder mutation in Iceland, was found in 0.4-
0.6% of unaffected Icelanders, 7.7- 8.5% of breast cancer cases that had not been selected on the basis of family
history or age of onset, 6-7.9% of ovarian cancer cases[85-87] and 40% of breast cancers occurring in males.[88]
Founder Mutations and Penetrance
The Ashkenazi founder mutations (BRCA1 mutations 185delAG and 5382insC, and BRCA2 mutation 6174delT)
and the Icelandic founder mutation (BRCA2 999del5) have been used for penetrance analysis. In addition to the
increased likelihood of finding a statistically useable number of BRCA1 and/or BRCA2 mutations in these
populations, these founder mutations also allow examination of penetrance in a minimally heterogeneous
genetic background, providing insights into potential genetic and/or environmental modifiers of BRCA1 and
BRCA2 mutation-associated cancer risks. In most studies, cancer risks in carriers of these founder mutations are
indeed lower when patients are not selected for family history, although the range of penetrance estimations in
different studies is broad. Some show age-specific cumulative risks for breast cancer in these carriers to be 26-
60%,[74,75,89-93] whereas others found higher risks, up to 80%.[43,44,85,93] These four founder mutations are associated
with a similarly broad range of ovarian cancer risks (12-40%) by the age of 70 years.[44,89,93,94]
Such population-specific genetic risk assessments already affect the clinical testing options available to high-
risk families. For example, individuals of Ashkenazi Jewish ancestry may be advised to seek genetic testing for
only three high-frequency BRCA1 and BRCA2 founder mutations before considering the more expensive
complete sequence analysis of both genes.[95,96] The efficiency of this strategy has prompted numerous hunts for
similar high-frequency mutations in other ethnic groups, with some success.
Mutations in Non-founder Populations
Although founder populations can be useful for studying genetic diseases with minimal background
heterogeneity, not all cancer patients are descended from such populations. For example, patients of African
ancestry have less frequent but more aggressive breast cancers than other populations, whether they live in
Africa or elsewhere in African diaspora populations.[97,98] Yet understanding the contribution of BRCA1 and
BRCA2 to populations of African ancestry poses unique challenges that cannot be completely anticipated from
the assumptions practiced in analysis of founder populations.
Traditionally, modern humans were thought to have arisen from a small population in Africa during the late
Pleistocene, replacing other archaic Homo taxa.[99-101] However, more recent evidence from mtDNA and non-
recombining Y-chromosome sequences suggest a more complex 'mosaic' of multiple origins of the modern
Homo.[102] In all cases, models suggest one or more bottleneck events associated with human migrations out of
Africa[100,103] (Figure 2), such that emigrating populations carry only subsets of the genetic diversity in Africa-
originating populations.
Figure 2.
Mercator projection of the Earth illustrating the "out of Africa" theory of early human migrations. It is
suggested that human origins were in eastern Africa, and then different groups migrated to populate other parts
of Africa, Europe and Asia, Australia and the Americas.

African populations show significantly higher levels of genetic diversity than other populations, reflected in
over 2,000 distinct ethnic groups and languages.[104-106] Indeed, there is greater genetic diversity within and
between different African populations than between African and Eurasian populations.[107,108] During the Atlantic
slave trade from the 15th to the 19th century, over 45 ethnic groups were brought to the Americas from African
regions ranging from Senegambia to west Central Africa, and even some groups from south-east Africa.
Additionally, modern descendants from these groups carry genetic admixtures of roughly 20% non-African
origin.[109,110]
Founder mutations have been difficult to identify in African and African-American populations, perhaps partly
due to the potentially high background genetic diversity of the populations examined, and possibly in part
because of the paucity of studies focused on these populations. One potential founder mutation, BRCA1
943ins10, has been identified in patients from Washington DC, Florida, South Carolina and Côte d'Ivoire
(formerly known as the Ivory Coast).[111,112] Although haplotype analysis demonstrates that this mutation
probably has a single origin and does not represent a mutational hot spot, no study has determined the
prevalence of this mutation in any African or African-American population. Several other potential founder
mutations have been proposed because of anecdotal recurrence, but few have been examined for shared
haplotypes, and none has been examined for population prevalence. If one does emerge as a true founder
mutation, it is unlikely that it will constitute a large proportion of all BRCA1 and BRCA2 mutations within a
population, in contrast to the founder mutations associated with the Ashkenazi and Icelandic populations.
Most studies that have described the population and family risks associated with inherited BRCA1 and BRCA2
mutations have used primarily Caucasian populations, leaving patients of African ancestry understudied.
Additionally, phenotypic similarities between breast cancers in Africans and African Americans and in BRCA1
mutation carriers suggest a potential distinctive genetic contribution to breast cancer risk and/or aetiology in
patients of African ancestry. Although breast cancers occur less frequently in patients of African ancestry than in
other groups, they tend to occur at earlier ages and are more frequently associated with aggressive tumour
features, such as comparatively high frequencies of medullary or atypical medullary carcinoma, poor
differentiation, aneuploidy, p53 mutations and oestrogen receptor-negative and progesterone receptor-negative
status (reviewed previously[112,113]). These features are in many ways similar to features associated with BRCA1
mutation carriers.[32,114-116]
Some of these general descriptions of BRCA1-associated tumours have been associated with tumour categories
defined by microarray analysis. Perou and colleagues examined the expression pattern of thousands of genes
from numerous breast tumours, and found that they fell into discrete clusters: one that looked like normal breast
cells, one that was associated with overexpression of the growth factor receptor gene ERBB2 (also known as
HER2 and neu), one associated with a basal epithelial cell-type expression pattern, and two associated with
luminal epithelial cell-type patterns.[117,118] Strikingly, tumours from BRCA1 mutation carriers have
predominantly basal-like expression patterns, consistent with immunohistological patterns and poor prognoses,
[119]
and sporadic tumours with basal-like expression patterns frequently exhibit reduced levels of BRCA1
expression.[120,121] Likewise, these aggressive basal-like tumours occur with higher frequency in premenopausal
African-American patients than other groups, potentially explaining, at least in part, the higher frequency of
breast cancer mortality among African Americans.[122] Thus, although BRCA1 mutations seem to occur with
similar or lower frequency among African Americans than in other groups,[7,80,123-126] BRCA1-associated
pathways may have an especially important role in breast cancer development in patients of African ancestry,
perhaps pointing the way to genetic or epigenetic modifiers of BRCA1 activity.
Conclusions
The benefits of population genetic analysis of BRCA1 and BRCA2 could lie well beyond the hunt for high-
frequency founder mutations. These studies could be the keys to several outstanding problems in risk
assessment and genetic analysis. First, the option of genetic testing for BRCA1 and BRCA2 mutations is
underused by some ethnic groups, in part because of cultural attitudes toward health care. It is therefore of great
importance to be able to describe the genetic risks and testing benefits particular to every ethnicity, particularly
underserved groups.[127]
Second, most reported deleterious mutations in BRCA1 and BRCA2 are exonic lesions that are predicted to
result in protein truncation. Others might be mutations in consensus splice donor or acceptor sites, or one of the
few known deleterious missense mutations.[128] Yet in many populations the majority of patients will also carry
one or more clinically unclassified genetic variants with unknown effects on gene function. It is vital to
determine which of these variants are benign polymorphisms and which could contribute to cancer risk.
Third, several statistical models can be used to predict the likelihood of carrying a BRCA1 or BRCA2 mutation
on the basis of personal and family history of breast and/or ovarian cancer. Yet most tested individuals that are
predicted to have a high probability of being mutation carriers have no identifiable BRCA1 or BRCA2
mutations.[28] In the absence of evidence for other high-penetrance cancer risk mutations,[129,130] this could be due
partly to the inadequacy of current testing methods to detect all potential deleterious mutations.[20] As discussed
previously, most BRCA1 and BRCA2 mutations are predicted to result in protein truncation or to disrupt
canonical splice-site sequences, whereas some result from large genomic rearrangements and a few represent
known missense mutations. To date, there has been no systematic study to identify non-obvious mutations that
affect BRCA1 or BRCA2 gene transcription or mRNA processing, either because such mutations could lie far
from the genes' exons, or because the potential deleterious effect is not always clear from the nature of the base
substitution. Although there is little evidence that such potential categories of mutation have a significant role in
BRCA1-associated and BRCA2-associated breast cancer risk, these mutation categories have been identified in
other disease-associated genes, and there is interest in characterizing the potential protein functional effects of
many unclassified sequence variants identified during genetic testing. Additionally, there are elegant models
suggesting much inherited breast cancer risk could come from non-Mendelian, polygenic effects of low-
penetrance genes not necessarily linked to BRCA1 or BRCA2 (Refs 10,131). Although such mutations are
unlikely to explain much non-BRCA1-associated or non-BRCA2-associated familial relative risk, they could
contribute significantly to the population-attributable fraction of cancer risk.[132] Population genetic studies could
be the key to identifying deleterious mutations with hidden locations or hidden significance, determining
whether low-penetrance mutations in BRCA1 or BRCA2 exist and whether they contribute to cancer risk
through different aetiologies, and identifying genetic modifiers that affect BRCA1 and BRCA2 mutation
penetrance.
Fourth, much of our current understanding of the variety and penetrance of deleterious BRCA1 and BRCA2
mutations has come from studies in which test cohorts that have the greatest likelihood of including many
mutation carriers, because of early age of onset or multiple affected family members, were chosen. Yet in a
typical clinical setting BRCA1 and BRCA2 mutation testing is recommended for patients with a range of
mutation likelihoods, from moderate to high. Surprisingly, little information is available for gauging the
prevalence of BRCA1 and BRCA2 mutations in cancer patients in a typical risk-assessment setting. The tools of
population genetics are necessary to determine the true contribution of BRCA1 and BRCA2 mutations to cancer
risk in the most relevant populations.
The BRCA1-associated and BRCA2-associated risks are different in geographical and historically defined
groups. These differences make clear the importance of assessing a patient's risk with respect to her (or his) own
genetic context. As the genetic stories of different populations are unfolded, we will see how evolving scientific
tools and changing working assumptions of population genetics can help guide our understanding of clinically
relevant BRCA1 and BRCA2 gene functions.
Sidebar: Mutation Screening in Patients
Several models have been devised, on the basis of personal and family cancer history and mutation-prevalence
tables, to predict a patient's likelihood of carrying a BRCA1 or BRCA2 mutation. The BRCAPRO model
assumes Mendelian inheritance of the autosomal dominant BRCA1 or BRCA2 mutations,[133,134] whereas the
breast and ovarian analysis of disease incidence and carrier estimation algorithm (BOADICEA) estimates the
likelihood of BRCA1 and BRCA2 mutations in a way that accounts for polygenic, low-penetrance factors and
BRCA1 and BRCA2 modifiers that are known to contribute to some familial breast and/or ovarian clusters.[129,135]
These and other models have been compared and reviewed elsewhere.[133,136-138] As always, the most useful
models for predicting patient risk will include estimates of both mutation frequency and mutation penetrance
(see below), and these may differ in different ethnic or geographic populations.[139] Parameters for each model
should be adjusted accordingly in different clinical settings.
Individuals seeking genetic testing for BRCA1 and BRCA2 mutations in the United States are screened by
Myriad Genetics, or in laboratories with rights licensed by Myriad. Unless patients are specifically interested in
a known family mutation or high-frequency mutations that are specific to certain ethnic groups, both genes are
typically sequenced entirely and, additionally, tested for some recurring BRCA1 rearrangements.[19,140-142] Outside
of the United States, mutation screening is not necessarily performed by Myriad, but in different laboratories
that are established according to guidelines of individual countries. In the United Kingdom, for example,
BRCA1 and BRCA2 mutation testing is offered by regional clinics run by the National Health Service in cases in
which patients meet family history criteria set by a national standard, as determined by their physicians.
Sidebar: Using Founder Mutations to Identify Disease-associated Genes
As founder mutations occur in the context of single haplotypes, and founder populations have less genetic
diversity than more outbred populations, it is efficient to use founder populations in which certain diseases are
unusually prevalent to identify genes that are associated with inherited disease predisposition. In such
populations, the common haplotypes that are linked to causative mutations may be detected not only in affected
members of high-risk families, but also, to some extent, in unrelated families within the population. This
reduction of genetic variability of causative mutations has proved fruitful in identifying disease-associated
genes in founder populations. The Finnish population, for example, is descended from a small number of
founders and there has been little immigration over the past 80-100 generations. As a result, the Finnish
population have an unusually high frequency of several inherited diseases (reviewed by de la Chapelle and
Wright[143]). This population has enabled the identification of founder mutations and the cloning of genes
responsible for several disorders, such as diastrophic dysplasia, progressive myoclonuns epilepsy and chloride
diarrhoea.[143]
Reprint Address
Olufunmilayo I. Olopade; E-mail: folopade@bsd.uchicago.edu .
James D. Fackenthal, Olufunmilayo I. Olopade, Department of Medicine and Center for Clinical Cancer
Genetics, University of Chicago, Chicago, Illinois

BRCA1 and BRCA2 Pathways and the Risk of Cancers Other Than Breast or Ovarian
Please note that on June 29, 2005 the incorrect text was posted for the article, "BRCA1 and BRCA2 Pathways and the Risk of
Cancers Other Than Breast or Ovarian". The text has been corrected.
Abstract
Objective: Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer.
Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic
abnormalities occur in all cancers, so BRCA-related pathways are critical because they serve to safeguard genetic content. Although
protecting genetic information is a general function, BRCA-related pathways seem largely specific to preventing breast and ovarian
cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific
clinical effects.
Data Sources, Data Extraction, Data Synthesis: The author collected data published in > 30 epidemiologic studies on the incidence
of cancers other than breast or ovarian in mutation carriers and in large populations eligible for mutation testing. Data were extracted
and used directly as published whenever possible with a minimum of statistical manipulation.
Conclusions: Although mutations target breast and ovary, a broader spectrum of cancers also occur with statistically significant
elevated frequencies. Risks for "all cancers except breast or ovary" are elevated, with some population subgroups differing with regard
to how frequently elevated risks were found at individual sites. Additional sites at risk included stomach, pancreas, prostate, and colon.
The increased risk ranged from about 20% to 60%, with the greatest increases in risk in stomach and pancreas. The collected data
show BRCA-pathway functions are probably required at multiple sites, not just in breast or ovary. Known interactions and
relationships among BRCA-related pathways strongly support the idea that their inactivation provides growth or survival advantages
for a variety of cancers. The data suggest applying an increased level of clinical alertness to those with defects in BRCA-related
pathways. Identifying molecules that confer growth or survival advantages to BRCA-related cancers may provide broadly useful
targets for chemotherapy or chemoprevention.
Introduction
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Some female
carriers of inherited mutations in BRCA1 or BRCA2 genes have lifetime risks for breast cancer exceeding 80%.
BRCA-related pathways safeguard genetic content, and a very large fraction of human cancers have abnormal genetic content.
BRCA1 and/or BRCA2 are involved in pathways important for DNA damage recognition, double-strand break repair, checkpoint
control, transcription regulation, and chromatin remodeling. These functions are essential and important for all cell types. Despite the
general nature of BRCA functions, tumors in mutation carriers predominantly target breast and ovary. A major problem is that the
broad theoretical importance of BRCA-related pathways conflicts with the specific targeting of cancers to breast and ovary. Some
observational studies report elevations of the risk for certain cancers besides breast or ovarian cancer in BRCA1 or BRCA2 mutation
carriers, but other studies conflict.
Although mutations in BRCA-related pathways may increase risk for sporadic or hereditary cancers other than breast or ovarian, the
risks for these additional cancers may be smaller than those for breast or ovarian cancer; they may show wider variation; they may
require large populations to measure; and they may involve proteins elsewhere in the pathways.
Carriers of mutations in BRCA1 and BRCA2 are relatively infrequent in the general population, and BRCA mutations are thought to
be involved in at most 5% to 10% of all breast cancers. Mutations of genes encoding ATM and CHEK2 or mutations leading to EMSY
amplification also affect BRCA pathways. These changes occur more frequently than BRCA1 or BRCA2 mutations in the general
population, suggesting inactivation of BRCA-related pathways is probably associated with significantly higher percentages of cancers.
Fortunately, data exist from many thousands of high-risk individuals who were not identified mutation carriers but who were eligible
for mutation testing. These data would include all mutations that affect BRCA pathways, and some studies provide a built-in control
because they also include those who were not eligible for mutation testing.
I collected data published in more than 30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation
carriers or in large populations eligible for mutation testing. Results of meta-analyses show that the loss of BRCA gene function
provides growth or survival advantages to a broader spectrum of tumors, including stomach, pancreas, prostate, and colon.
Thus, BRCA pathways function at multiple sites throughout the body, not just in breast or ovary. This does much to resolve a major
conflict between the mechanisms of BRCA pathways participation in tumor suppression and clinical observations. The data suggest
there ought to be increased clinical awareness for those with defects in BRCA-related pathways. Identifying molecules that confer
growth or survival advantages to tumors in those with BRCA pathway deficits may provide helpful targets for chemotherapy or
chemoprevention.
Discussion
The incidence of cancers other than breast or ovarian was a peripheral issue in most studies, but the high quality of the data makes the
present analysis feasible. Although the sites that show increased risk for cancer may vary among studies, essentially all applicable
studies support the idea that damage to BRCA-related pathways increases overall cancer risks beyond breast and ovarian ( Table 1 and
Figure 1). Figures 1 and 2 also show some specificity in the organs at risk because an increase in cancer susceptibility was found more
frequently for the stomach, pancreas, prostate, and colon/rectum. The amount of the increase in risk ranges from about 20% to about
60%.
In comparison to breast and ovarian cancers, the frequencies of additional cancers associated with BRCA1 or BRCA2 pathway
mutations are lower. These include some cancers that have a high incidence rate in the general population and are thus not unexpected
in families with BRCA mutations. This makes it essential to review a large amount of data. Generally in comparing studies in Table 1
that included BRCA mutation testing, those studies which involved the greatest number of mutation carriers reported the largest
number of different sites for cancers beyond breast and ovarian. The size of the effect can be debated in some tissues. But loss of
BRCA-related pathways more generally favors tumor growth or improves tumor survival beyond the breast and ovary. Moreover,
BRCA-related gene pathways function in numerous sites throughout the body, not just in breast or ovary.
Despite the interrelationships of BRCA1 and BRCA2,[35] different BRCA1/BRCA2 mutations could have different functional effects.
Table 1 and Table 2 and Figures 1 and 2 suggest that either mutation increases risk for a variety of cancers. Many studies tested only
for BRCA1 or BRCA2 founder mutations and were unable to detect mutations of different types, which now make up a substantial
minority of the total set. None of the studies tested for EMSY overexpression, because EMSY was unknown at the time of the studies.
In significant percentages of sporadic breast and ovarian cancers, overexpression of EMSY may be functionally equivalent to loss of
BRCA genes. Heterozygous ATM mutations have also been associated with increased risk for breast cancer and potentially for other
cancers as well.[39] Thus, the risk for a variety of cancers can be evaluated by considering the whole BRCA pathway, not just BRCA1/2
genes. These arguments also justify this report's use of data not only from BRCA mutation carriers but also from people eligible for
BRCA mutation testing. The percentages of the population with a defect in the BRCA pathway other than in BRCA genes may be
significantly larger than the percentages of people with BRCA1 and BRCA2 gene mutations. This implies that other components of
BRCA pathways may be targeted in some sporadic cancers. This properly shifts the focus from an individual gene to the pathway or
the local area of the network in which the gene resides.
Other inherited gene mutations, including those in PTEN and p53, also predispose to breast cancer and would contribute to relative
risks for other cancers. These mutations have a rarer incidence than those in BRCA genes, and a case can be made that their pathways
have some relationship to those involving BRCA1 and BRCA2.
Sporadic cancers are consistent with known mechanisms of BRCA gene actions.
A generalized susceptibility to a variety of additional tumors is consistent with current ideas of BRCA1 and BRCA2 functions. Figure
3 shows the evolving diagram of proposed functions and interactions among BRCA-mediated gene pathways. The figure summarizes
published functional implications and models of DNA damage responses involving BRCA1 and BRCA2. Mechanisms that sense DNA
damage activate protein kinases such as ATM or ATR, triggering a cascade of phosphorylation-dependent steps leading to cell-cycle
checkpoint arrest, DNA repair, or apoptosis. BRCA1, BRCA2, and Fanconi anemia (FA) proteins are involved in these steps. The
MRE-Rad50-Nbs1 complex indicated in the Figure also functions as a double strand break sensor that recruits ATM to broken DNA
molecules.[40] Figure 3 stresses that BRCA1 and BRCA2 are involved in pathways that regulate DNA repair, cell-cycle progression,
ubiquitylation, and apoptosis.
Figure 3.
Examples of interactions involving BRCA1 and BRCA2 proteins stressing the general nature of their functions and some interactions
with BRCA1. The exact order of events and understanding of these interactions are still evolving.

Inhibition of MYC action by interacting with BRCA1 may help explain why loss of BRCA function impacts some sporadic cancers.
BRCA1-IRIS or unrecognized factors may participate in determining tissue specificity to limit BRCA influences in other tumors or
they may significantly alter our current understanding. Moreover some relationships and interactions in Figure 3 are likely to occur
only in specific physiologic contexts. For example, MYC overexpression or BRCA mutation may have different effects depending on
when in development they occur because the genomic background is different.[38] Nonetheless, the above considerations may be
helpful in understanding involvement of BRCA-related pathways in limiting tumors in organs other than breast or ovary. The above
pathways and functional associations help explain the documented clinical associations.
It is possible that different populations in different geographical areas may have different susceptibilities. Sporadic cancers are
sensitive to diet and environmental exposure, and these cannot be controlled in any observational study. The possibility that
chemotherapy for breast or ovarian cancers induces secondary tumors more readily in mutation carriers cannot be excluded. Standard
chemotherapy and radiation regimens for breast cancer would increase risks for leukemia and other cancers. [10] Risk for (myeloid)
leukemia is statistically significantly elevated in the Evans study[6] but not in the Bermejo study.[9] Goldgar and colleagues[16] and
Harvey and Brinton[7] did not find an increased risk of leukemia associated with breast cancer.
One might expect that BRCA mutations would lower the age of onset of sporadic cancers. There are limited data on the age at onset of
sporadic cancer vs. incidence of other cancers. Harvey and Brinton[7] found a significant downward trend for risk vs. age for colon
cancer (RR = 1.6, 1.3, 1.1) and rectal cancer (RR = 1.9,1.1,1.0) for ages < 45, 45-54, and 55+. This is consistent with BRCA mutations
affecting the incidence/onset of colon cancer.
A lowered age at onset may be difficult to demonstrate more convincingly, particularly for slow-growing cancers such as colon cancer.
It is likely that screening practices vary widely among population groups within individual studies. Patients usually have no symptoms
or only nonspecific ones until their cancers reach a large size or spread to other organs. Current colon cancer screening misses many
early cases,[41] up to almost 85% by fecal occult blood testing. Sigmoidoscopy may miss over 92% of advanced colorectal neoplasia in
the proximal colon.[42] Screening for colon cancer is notorious for its poor compliance. BRCA mutations occur with comparatively high
frequency in Israel; yet in 2000, almost half the Israeli population was unaware of colorectal cancer screening, and only 38% had any
interest in participating. Thus, many cases of the disease are detected only at an advanced stage. [41] Colon cancer takes 20 to 40 years to
develop with no intermediate endpoints to measure rate of development after transformation. Long follow-up was not frequently done
in the studies reviewed so that slow-growing tumors might be missed.
Some cancers (such as prostate cancer) in BRCA mutation carriers or those eligible for mutation testing may not have distinct
histopathology. Despite the BRCA-relationship, some routes of cancer evolution could still be abolished because some checkpoint
mutations are lethal and limit diversity. The initiating oncogenic events may restrict ensuing pathways to limit the subsequent mutation
profile of the cancers that occur, pruning disease entities so that the surviving tumors do not differ histologically from sporadic
cancers.
Table 1. Epidemiologic Studies That Include Data on the Risk of "Other" Cancers

U.S. Preventive Services Task Force Issues Guidelines for BRCA Mutation
Testing
Sept. 9, 2005 — The U.S. Preventive Services Task Force (USPSTF) recommends against routine genetic screening or counseling for
breast and ovarian cancer susceptibility except for women with increased risk by family history, according to a statement published in
the Sept. 6 issue of the Annals of Internal Medicine.
"Certain specific family history patterns are associated with an increased risk for deleterious mutations in the BRCA1 [breast cancer
susceptibility gene 1] or BRCA2 [breast cancer susceptibility gene 2] gene," write Alfred O. Berg, MD, MPH, from the University of
Washington in Seattle, and colleagues from the USPSTF panel. "Both maternal and paternal family histories are important."
The USPSTF reviewed MEDLINE from 1966 through Oct. 1, 2004, Cochrane Library databases, reference lists, reviews, Web sites,
and expert opinions, and they rated the quality of available evidence. The statement summarizing the USPSTF recommendations on
genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility, as well as supporting scientific
evidence, is available online at the USPSTF Web site: http://www.preventiveservices.ahrq.gov, and the recommendation is available at
the National Guideline Clearinghouse Web site: http://www.guideline.gov.
Women whose family history is not associated with an increased risk of harmful mutations in BRCA1 or BRCA2 should not have
routine referral for genetic counseling or routine BRCA testing. This is a grade D recommendation.
For non–Ashkenazi Jewish women, family history suggesting increased risk includes having two first-degree relatives with breast
cancer, one of whom received the diagnosis at age 50 years or younger; a combination of at least three first- or second-degree relatives
with breast cancer regardless of age at diagnosis; a combination of both breast and ovarian cancer in first- and second- degree
relatives; a first-degree relative with bilateral breast cancer; a combination of at least two first- or second-degree relatives with ovarian
cancer regardless of age at diagnosis; a first- or second-degree relative with both breast and ovarian cancer at any age; or a history of
breast cancer in a male relative.
For Ashkenazi Jewish women, family history suggesting increased risk includes having one first-degree relative or two second-degree
relatives on the same side of the family with breast or ovarian cancer. In the general population, approximately 2% of adult women
meet these criteria for increased risk family history.
The USPSTF panel found fair evidence that women not meeting these criteria for increased risk family history have a low risk for
developing breast or ovarian cancer associated with BRCA1 or BRCA2 mutations. Therefore, the potential benefit from routine
screening of these women for BRCA1 or BRCA2 mutations or from routine referral for genetic counseling would be negligible.
However, the USPSTF found fair evidence that routine referral and testing of these women could result in significant adverse ethical,
legal, and social consequences. Prophylactic surgery, chemoprevention, intensive screening, and other interventions have known
potential harms, the magnitude of which the USPSTF panel estimated to be small or greater. For women not meeting criteria for
increased risk family history, the USPSTF therefore concluded that the potential harms of routine referral for genetic counseling or
BRCA testing outweigh the benefits.
The USPSTF recommendation for genetic counseling and evaluation for BRCA testing in women with increased risk family history is
a grade B recommendation. The evidence was fair that these women have an increased risk for developing breast or ovarian cancer
associated with BRCA1 or BRCA2 mutations, so the USPSTF panel concluded that they would benefit from genetic counseling by
suitably trained healthcare providers to facilitate informed decision making about testing and further prophylactic treatment.
Although the evidence was insufficient to determine the benefits of chemoprevention or intensive screening in improving health
outcomes in these women who have positive test results for harmful BRCA1 or BRCA2 mutations, the evidence was fair that
prophylactic surgery for these women significantly lowers the incidence of breast and ovarian cancer. The potential benefits of referral
and discussion of testing and prophylactic treatment may therefore be significant for these women.
The USPSTF also determined that evidence was insufficient concerning important adverse ethical, legal, and social consequences that
may result from counseling and screening of high-risk women. Although there are known harms of prophylactic surgery, the USPSTF
estimated that the magnitude of these potential harms is small. The panel therefore determined that the benefits of referring high-risk
women to suitably trained healthcare providers outweigh the harms.
The panel stresses that these recommendations apply only to women not diagnosed as having breast or ovarian cancer, and not to men.
Women with a family history of breast or ovarian cancer that includes a relative with a known harmful BRCA1 or BRCA2 mutation
should be referred for genetic counseling.
The USPSTF guidelines note the absence of empirical evidence regarding the level of risk for a BRCA mutation that merits referral for
genetic counseling. Although computational software is available to predict the risk for BRCA mutations associated with breast cancer,
ovarian cancer, or both, these tools have not been validated in the general population.
"Not all women with a potentially deleterious BRCA mutation will develop breast or ovarian cancer," the authors write, noting that in
women with clinically important BRCA mutations, the probability of developing breast or ovarian cancer by age 70 years is estimated
to be 35% to 84% for breast cancer and 10% to 50% for ovarian cancer. "Appropriate genetic counseling helps women make informed
decisions, can improve their knowledge and perception of absolute risk for breast and ovarian cancer, and can often reduce anxiety."
Genetic counseling should be administered by a suitably trained healthcare provider, and in addition to counseling, it should include
elements of risk assessment, pedigree analysis, and, when appropriate, recommendations for testing for BRCA mutations in the patient,
affected family members, or both. Because genetic testing may have adverse ethical, legal, and social consequences, including
insurance and employment discrimination, counseling should address these issues.
In women with BRCA1 or BRCA2 mutations, prophylactic mastectomy or oophorectomy decreases the incidence of breast and ovarian
cancer, but evidence is inadequate for improved survival. Although chemoprevention with selective estrogen-receptor modulators may
reduce the incidence of estrogen receptor–positive breast cancer, it may also have adverse effects, including pulmonary embolism,
deep venous thrombosis, and endometrial cancer.
Limitations of the underlying evidence, according to Heidi D. Nelson, MD, MPH, and coauthors, are that "no data describe the range
of risk associated with BRCA mutations, genetic heterogeneity, and moderating factors; studies conducted in highly selected
populations contain biases; and information on adverse effects is incomplete."
"A primary care approach to screening for inherited breast and ovarian cancer susceptibility has not been evaluated, and evidence is
lacking to determine benefits and harms for the general population," the authors conclude.
Ann Intern Med. 2005;143:355-361

Prophylactic Surgery Reduces Cancer Risk and Lowers Mortality in BRCA

Mutation Carriers
August 31, 2010 — A large new study has confirmed the benefits of prophylactic mastectomy and salpingo-
oophorectomy in women with BRCA1 and BRCA2 mutations. Women who underwent the prophylactic surgery
had a greatly reduced risk for breast or ovarian cancer and a reduction in cancer-related mortality.
The findings appear in the September 1 issue of the Journal of the American Medical Association.
This study adds evidence supporting the benefits of preventive surgery — that it can reduce the risk for cancer-
related mortality and for breast/ovarian cancer developing in the first place, explained senior author Timothy
Rebbeck, PhD, professor of epidemiology at the University of Pennsylvania School of Medicine in
Philadelphia.
Dr. Rebbeck and colleagues investigated a cohort of nearly 2500 women with BRCA1 or BRCA2 mutations,
10% of whom chose to undergo a risk-reducing mastectomy and 38% of whom chose a risk-reducing salpingo-
oophorectomy.
No breast cancers were diagnosed in the women who underwent mastectomy during the 3 years of prospective
follow-up. However, 7% of those who did not undergo a prophylactic mastectomy during a similar follow-up
period were diagnosed with breast cancer.
There were no cases of ovarian cancer events during the 6 years of prospective follow-up in BRCA2 carriers
without previous breast cancer who underwent salpingo-oophorectomy. Conversely, 3% of women who did not
undergo the procedure over a similar follow-up period were diagnosed with the disease.
Among BRCA1 carriers with a previous diagnosis of breast cancer, undergoing a salpingo-oophorectomy was
associated with a reduced risk for ovarian cancer (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 -
0.63); there were no cases diagnosed in BRCA2 carriers.
Overall, results showed that, compared with women who did not undergo prophylactic salpingo-oophorectomy,
those who underwent the procedure had an overall lower risk for ovarian cancer, including those with previous
breast cancer (6% vs 1%; HR, 0.14; 95% CI, 0.04 - 0.59) and those without previous breast cancer (6% vs 2%;
HR, 0.28; 95% CI, 0.12 - 0.6); a lower risk for first diagnosis of breast cancer in BRCA1 carriers (20% vs 14%;
HR, 0.63; 95% CI, 0.41 - 0.96) and BRCA2 carriers (23% vs 7%; HR, 0.36; 95% CI, 0.16 - 0.82); lower all-
cause mortality (10% vs 3%; HR, 0.40; 95% CI, 0.26 - 0.61); lower breast-cancer-specific mortality (6% vs 2%;
HR, 0.44; 95% CI, 0.26 - 0.76); and lower ovarian-cancer-specific mortality (3% vs 0.4%; HR, 0.21; 95% CI,
0.06 - 0.80).
Data for Surveillance Group Limited
The women who opted not to have prophylactic surgery were counseled to undergo intensive screening.
Although surveillance isn't prevention, it can result in earlier detection and improved survival, but the
nonsurgery group of the study was not specifically evaluated for surveillance practices, said Dr. Rebbeck.
"We don't have data on the survival or mortality in women who underwent optimal screening," he told
Medscape Medical News. "Having said that, the breast cancer risk reduction among women in the
oophorectomy group is substantial but comparable to that in the general population of women who took
tamoxifen."
There are no data to date for women with BRCA1/2 mutations and primary prevention of breast cancer with
tamoxifen use, he added. "While there are no comparison data available, it may be possible that the risk
reduction by oophorectomy is comparable to that of other measures."
But Dr. Rebbeck emphasized that an important point to remember is that oophorectomy is primarily
recommended to reduce ovarian cancer risk or death, not breast cancer. "Women should be using oophorectomy
as an ovarian cancer prevention tool — the benefit to breast cancer is just a side benefit," he said.
Importance of Counseling, Fear of Genetic Testing
It is important to identify and counsel women who have a family history of breast cancer, so that they will better
understand their risks and options, and ways to reduce those risks, note the authors of an accompanying
editorial.
"At a minimum, primary care clinicians should be familiar with the American Society of Clinical Oncology or
National Comprehensive Cancer Network guidelines and should be able to refer at-risk patients to a genetic
counselor," write Laura Esserman, MD, MBA, from University of California, San Francisco, and Virginia
Kaklamani, MD, DSc, from Northwestern University, Chicago, Illinois.
The editorialists point out that now that there are better data available on the potential outcomes of these
interventions, women can make more informed choices about whether to opt for prophylactic surgery or
intensive surveillance.
But even though the techniques for prophylactic surgery and cosmetic options have improved, many women
still might not opt for this. In such cases, there are other approaches that are less invasive than surgery but more
aggressive than surveillance, explained Dr. Kaklamani.
"We have chemopreventive agents such as tamoxifen that can help, and there are other agents that are being
tested, such as PARP inhibitors," she told Medscape Medical News.
In addition, some people fear the implications that positive genetic tests, including those for BRCA mutations,
can have on their insurance premiums. The Genetic Information Nondiscrimination Act of 2008 was designed to
protect people from insurance and employer discrimination on the basis of genetic tests, and Dr. Kaklamani
emphasized the importance of educating women about this.
"There are laws that protect us from insurance discrimination from genetic testing and, with this study, we now
know that procedures that we recommend have a positive impact on survival," she said.
Evidence Added
The study adds to the growing body of literature concerning the benefits of prophylactic surgery for women
with BRCA1/2 mutations. As previously reported by Medscape Medical News, 4 separate analyses showed that
having a bilateral mastectomy reduced the risk for breast cancer by 90%.
Another study found that women carrying the BRCA gene mutation who underwent a prophylactic mastectomy
reduced their risk for breast cancer to less than 1%. Although estimates vary, mutation carriers have an
approximate lifetime risk for breast cancer that ranges from 56% to 84%.
Improved Research Mechanisms Needed
"The discovery of biomarkers that identify high-risk individuals for a specific disease and integration of these
biomarkers into clinical practice enables the systematic study of these populations — and development and
testing of interventions to reduce their risk," write the editorialists.
They note that the study required more than 20 collaborating clinical centers to collect data from thousands of
women who participated in the research, and point out that better methods are needed.
Improved mechanisms are needed to study and evaluate "the introduction of new tests, like BRCA gene
mutation testing, and to capture key pieces of de-identified information — such as the uptake of testing, results,
clinical decisions, and outcomes — so that clinicians and researchers can continually learn from their
experience," they write.
The study was supported by grants and funding from the Public Health Service, the University of Pennsylvania
Cancer Center, the Cancer Genetics Network, the Marjorie Cohen Research Fund, SPORE grant from the
Dana-Farber/Harvard Cancer Center, the US Department of Defense, the Utah Cancer Registry and the Utah
State Department of Health, Nebraska State Cancer and Smoking-Related Diseases Research Program, Cancer
Research UK, National Cancer Institute, and the National Institute for Health Research. Olufunmilayo I.
Olopade, MD, a coauthor of the study, from the University of Chicago Medical Center in Illinois, has received
funding as the Doris Duke Distinguished Clinical Scientist. The other study authors and the editorialists have
disclosed no relevant financial relationships.
JAMA. 2010;304:967-975, 1011-1012.