Professional Documents
Culture Documents
(2017) 18:27
DOI 10.1007/s11864-017-0468-y
Keywords BRCA1/2 I ATM I CHEK2 I PALB2 I Multiple-gene testing I Hereditary breast and ovarian cancer syndromes I
PARP inhibitor therapy
Opinion statement
The advent of multiple-gene germline panel testing has led to significant advances in
hereditary breast and ovarian cancer risk assessment. These include guideline-specific
cancer risk management recommendations for patients and their families, such as screening
with breast magnetic resonance imaging and risk-reducing surgeries, which have the
potential to reduce substantially the morbidity and mortality associated with a hereditary
cancer predisposition. However, controversy remains about the clinical validity and
actionability of genetic testing in a broader patient population. We discuss events leading
to the wider availability of commercialized multiple-gene germline panel testing, the recent
data that support using this powerful tool to improve cancer risk assessment and reduction
strategies, and remaining challenges to clinical optimization of this new genetic technology.
Introduction
Over the past decade, significant advances in clinical that had several members with early-onset breast can-
cancer genetics have strengthened personalized cancer cer [1]. Although only about 5 to 10% of women with
medicine. The breast cancer susceptibility genes, breast cancer have an identifiable genetic predisposi-
BRCA1 and BRCA2 (BRCA1/2), were identified more tion, up to 20 to 30% of those with a family history of
than 20 years ago after extensive studies of families breast and ovarian cancer have a mutation in a breast
27 Page 2 of 10 Curr. Treat. Options in Oncol. (2017) 18:27
cancer susceptibility gene, primarily BRCA1/2 [1, 2]. of agents such as poly (ADP-ribose) polymerase
The discovery of these two genes and subsequent (PARP) inhibitors. In the current era of massively
clinical availability of germline BRCA1/2 gene testing parallel next-generation sequencing, technologies
enabled insights into the natural history of BRCA1/2 that deliver more genetic information at a lower cost
mutation-associated cancers and development of than ever before, the clinical implications of genetic
evidence-based risk-reduction guidelines for muta- testing will exponentially increase. We summarize
tion carriers. Furthermore, it advanced the field of recent progress in clinical cancer genetics and high-
targeted cancer therapeutics with the development light research priorities.
Table 1. Estimated cancer risks and guidelines for breast cancer-associated genes on multigene germline panels
Gene Breast cancer Other cancer risks and Clinical practice guidelines References
relative risk syndromes
ATM Two to three-fold Ataxia telangiectasia National Comprehensive Cancer [13, 35, 37]
(c.7271T9G missense syndrome in homozygotes; Network (NCCN): Screening with
mutation with colon, pancreas, prostate breast MRI; consider RRM based
estimated 60% risk of (possibly family history on family history
breast cancer by age 80) dependent)
BRCA1 10-fold Ovarian American Cancer Society (ACS) and [8, 13, 18,
NCCN: Screening with breast MRI, 35, 38]
recommend RRBSO, discuss RRM
BRCA2 10-fold Ovarian, pancreatic, prostate, NCCN: Screening breast MRI, [8, 13, 18,
melanoma recommend RRBSO, discuss RRM 35, 38]
CDH1 Fivefold (particular Gastric NCCN: Screening breast MRI; [13, 35,
association with consider RRM based on family 39–41]
lobular breast history
carcinoma)
CHEK2 Two to threefold Possible link with colorectal, NCCN: Screening breast MRI, [13, 35, 42,
(threefold risk with thyroid, lung (possibly Patient with first-degree relative with 43]
truncating mutation family history dependent) colorectal cancer, consider
1100delC) colonoscopy every 5 years at 40, or
10 years prior to age of cancer
diagnosis. Patient with no
first-degree relative with colorectal
cancer, consider colonoscopy every
5 years beginning at age 40
NBN Two to threefold Nijmegen breakage syndrome Consider screening breast MRI [35, 44, 45]
in homozygotes; possibly
ovarian
NF1 Two to threefold Central nervous system, Consider screening breast MRI [35, 46]
peripheral nerve sheath
PALB2 Three to fivefold Pancreas; possibly ovarian NCCN: Screening breast MRI, discuss [13, 35, 47]
RRM
PTEN At least fivefold Thyroid, endometrial NCCN: Screening breast MRI, discuss [13, 35, 48,
RRM 49]
STK11 At least fivefold Pancreas, colon, ovarian sex NCCN: Screening breast MRI [13, 35, 50]
cord-stromal
TP53 At least 10-fold Multiple sites including NCCN: Screening breast MRI, discuss [13, 35, 51]
adrenocortical, brain, RRM; whole-body MRI,
leukemia, sarcoma colonoscopy, complete blood
count, and other tests
RRBSO bilateral risk-reducing salpingo-oophorectomy, RRM risk-reducing mastectomy
determining that human genes in their natural form may not be patent-
ed [1]. The Supreme Court ruling in conjunction with rapid technolog-
ical advances in next-generation gene sequencing opened doors to a
competitive marketplace of commercialized multiple-gene germline pan-
el testing.
27 Page 4 of 10 Curr. Treat. Options in Oncol. (2017) 18:27
negative breast cancer [24•], and patients seen in high-risk cancer genet-
ics clinic settings [25–27, 28•].
A recent study by Tung and colleagues investigated the prevalence of
deleterious germline mutations in 25 cancer susceptibility genes among
patients with a personal history of breast cancer who were unselected for
family history. The study cohort comprised of 488 breast cancer patients,
with 49% of patients reported having a first- or second-degree relative
with breast or ovarian cancer (mean age at time of breast cancer diag-
nosis was 50.3 years, 7.8% of the patients were of Ashkenazi Jewish
descent, and 18% of the women had triple-negative breast cancer). Fifty-
five deleterious mutations were identified in 52 (10.7%) patients. While
30 (6.1%) of the patients had a germline BRCA1/2 mutation, 20 (4.1%)
of patients had a total of 21 deleterious mutations in non-BRCA1/2
breast cancer predisposition genes, including CHEK2 (n = 10), ATM
(n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, and NPN.
Notably, at least one variant of uncertain significance (VUS) was iden-
tified in 162 (32.2%) of women. Factors that significantly predicted
BRCA1/2 mutation carriage (including younger age at breast cancer
diagnosis, Ashkenazi Jewish heritage, triple-negative breast cancer, and
higher grade) did not predict carriage of a mutation in the other breast
cancer predisposition genes, when these genes were analyzed as a single
group [29]. Given the absence of predictive factors for carriage of non-
BRCA1/2 mutations, it may be that most or all breast cancer patients
will ultimately benefit from multiple-gene germline panel testing [29].
As testing costs fall and access grows, a major question is the clinical
utility of multiple-gene germline panel testing for cancer susceptibilty.
We prospectively enrolled and conducted multiple-gene germline panel
testing of patients who were appropriate candidates for HBOC screening
and who lacked deleterious BRCA1/2 mutations [26, 28•]. Among the
1046 participants, 63 BRCA1/2-negative patients harbored deleterious
mutations, most commonly in moderate-risk breast and ovarian cancer
genes (ATM, CHEK2, and PALB2) and the Lynch syndrome genes. Nearly
one third of mutation-positive patients (20 of 63) had mutations in
genes for which guidelines recommended a change in cancer screening
or prevention approaches (Table 1). Among patients with deleterious
mutations in low- to moderate-risk breast cancer genes, a management
change was recommended in one quarter of cases, with additional
implications for unaffected relatives [28•]. Our work and that of others
(Table 1) emphasize the clinical relevance of multiple-gene germline
panel testing for hereditary cancer risk.
Similarly, Idos and colleagues presented on the interim analysis of a
study assessing the yield of multigene panel testing versus expert genetic
opinion among 1000 patients with a ≥ 2.5% likelihood of carriage of a
deleterious gene mutation at the 2016 American Society of Clinical
Oncology Annual Meeting. A total of 11.6% patients tested positive for
at least one pathogenic variant, and 36.5% of the individuals had at
least one VUS. One quarter of patients with a pathogenic variant had a
gene mutation that was “missed” by expert opinion, several in a clini-
cally “actionable” gene with implications for these patients’ care [30].
Notably, patients with “missed” mutations lacked the classic phenotype:
Curr. Treat. Options in Oncol. (2017) 18:27 Page 7 of 10 27
Future directions
The landscape of clinical cancer genetics has dramatically changed in the recent
years; these advances have yielded concrete and comprehensive guidelines with
27 Page 8 of 10 Curr. Treat. Options in Oncol. (2017) 18:27
great potential to benefit patients and families at risk of HBOC. Research must
address gaps in the current landscape of clinical cancer genetics: one major
priority is to reduce the prevalence of reported VUS by sequencing larger and
more diverse populations. Population-based studies are essential to understand
the true prevalence of breast cancer susceptibility gene mutations in the general
population, outside of high-risk cancer genetics clinics. Furthermore, evidence-
based clinical guidelines for patients carrying such pathogenic gene mutations
can be implemented only if their prevalence and penetrance are better under-
stood. Another key approach is biomarker-driven clinical trials of targeted
agents such as PARP inhibitors for the treatment and prevention of hereditary
breast, ovarian, and other cancers.
Conflict of Interest
Anosheh Afghahi declares that she has no conflict of interest.
Allison W. Kurian has received research support through grants from Myriad Genetics, Ambry Genetics, and Invitae.
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