BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis William D. Foulkes

 Springer 2006
Familial Cancer (2006) 5:135–142
DOI 10.1007/s10689-005-2832-5
BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis
William D. Foulkes
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec,
Canada, H2W 1S6
Received 27 August 2004; accepted in revised form 9 February 2005
Key words: chemotherapy, hereditary breast and ovarian cancer, oncology, survival
BRCA1 and BRCA2 are important breast and ovarian cancer susceptibility genes, and mutations in these two genes
confer lifetime risks of breast cancer of up to 80% and ovarian cancer risks of up to 40%. Clinico-pathological
studies have identified features that are specific to BRCA1-related breast cancer, but this has been more difficult for
BRCA2-related breast cancer. Ovarian cancers due to BRCA1 or BRCA2 mutations cannot usually be distinguished
from their non-hereditary counterparts on morphological grounds, but micro-array data suggest that differences do
exist. Prognostic studies have shown that breast cancer in a BRCA1 mutation carrier is likely to have a similar, or
worse, outcome than that occurring in a BRCA2- or non-carrier of the same age. By contrast, most studies indicate
that women developing a BRCA1/2-related ovarian cancer have an improved survival compared with non-carriers,
particularly if they receive platinum-based therapy. In support of this, in vitro chemo-sensitivity studies have found
that human cells lacking BRCA1 may be particularly sensitive to cisplatinum and to other drugs that cause doublestrand breaks in DNA. Nevertheless, in breast cancer, little is known regarding clinically important differences in
response to chemotherapy between BRCA1/2 mutation carriers and non-carriers, and between different chemotherapeutic regimens within existing series of BRCA1/2 mutation carriers. There are no published prospective
studies. It is hoped that, in the near future, randomised controlled trials will be started with the aim of answering
these important clinical questions.
BRCA1 and BRCA2 are important breast cancer and
ovarian susceptibility genes, accounting for 2–4% of all
breast cancer and 5–10% of ovarian cancer worldwide.
A considerably higher percentage of mutation carriers
are found in some populations, particularly those where
religious, cultural or geographical factors may have
limited the flow of genes [1]. Identifying mutations in
these genes in women who are at risk of breast/ovarian
cancer, or who already developed a cancer, is now part
of routine clinical cancer genetics. Indeed, in the
Canadian province of Ontario, a large part of the
practice of medical genetics is now devoted to breast and
ovarian cancer risk assessment [2], and most cancer
centres have units devoted to hereditary cancer and/or
cancer risk assessment.
The purpose of this brief and selective review is to
highlight research into the effect of the presence or
absence of BRCA1 and BRCA2 mutations on (a) the
sensitivity in vitro to certain chemotherapeutic drugs;
and (b) the response to chemotherapy in patients with
breast or ovarian cancer. Clinical response to radiotherapy or hormonal therapy will not be discussed.
I hope to show how the presence of BRCA1/2 mutations
may come to influence the practice of oncology,
specifically the choice of chemotherapeutic agents. Most
oncologists do not use mutation status to guide therapy,
although there are early suggestions that this information can be useful, particularly if the decision whether or
not to give chemotherapy is a difficult one (i.e. on the
basis of tumour size and nodal status alone) [3].
Increasingly it is accepted that events early in the life
of a breast cancer can determine the long-term outcome
[4–6] and that BRCA1-related breast cancers have a
specific gene expression profile that can distinguish such
cancers from both BRCA2-related and non-hereditary
cancers [5, 7]. Additionally, gene expression profiles may
Correspondence to: William D. Foulkes ; Fax: +514-9348273; E-mail: [email protected]
determine response to certain chemotherapeutic agents
[8]. Therefore, it seems plausible that BRCA1 and
BRCA2-related breast cancers may possess gene expression profiles that will render these tumours particularly
susceptible to one type of chemotherapeutic regimen,
whereas they may be resistant to another. This is not
perhaps very different from the situation in nonBRCA1/2-related breast cancer, where similar analyses
will soon be possible, but the difference with hereditary
breast cancer is that the pre-existing inherited mutation
may favour a specific initial molecular effect (for
example, impaired double-strand DNA repair) or pathological pathway (expression of basal, rather than
luminal keratins) which is unlikely to be present in a
large sub-set of non-hereditary cancers. This could result
in class-based therapy, which may be more financially
and logistically practical than the much-discussed ‘individualized chemotherapy’.
Clinicopathological features of BRCA1/2-related
breast cancers
The purpose of this section is to illustrate the key
differences between three types of breast cancer:
BRCA1-related, BRCA2-related and non-hereditary.
This will serve as an introduction to the sections on
the in vitro and in vivo data that relate specifically to
response to chemotherapeutic agents. Differences in
responses that are observed are likely to be determined,
in part, by differences in gene expression profiles, which
are reflected in the different clinico-pathological features
of these three groups of breast cancers.
BRCA1-related breast cancers tend to be high-grade
[9], lymph node negative [10] tumours that do not
express estrogen receptors (ER), HER2 [11] or p27Kip1
[12], but do express p53 [13], cyclin E [14] and
cytokeratin (CK) 5/6 [15, 16]. A marker of tumour
vascularity known as glomeruloid microvascular proliferation (GMP), a feature of glioblastoma multiforme, is
significantly more likely to be present in BRCA1-related
cancers than in other types of breast cancer [17]. In
addition, MYC amplification appears to be much more
frequent in BRCA1-related breast cancer than in nonhereditary breast cancer [18, 19], and this knowledge,
when combined with TBX2 status, could possibly used
to predict the presence of a BRCA1 mutation [19].
Many of the features of BRCA1-related cancer
discussed above are shared with breast cancers that
have a basal epithelial phenotype [20, 21] but the true
significance of this phenotype is not yet known,
although most studies have shown that the basal
phenotype is associated with an inferior outcome [14,
22–24]. Whether or not this phenotype can be used to
determine what type of chemotherapeutic regimen
should be employed is an intriguing but unanswered
The situation for BRCA2 is more complicated: six
years ago, the Breast Cancer Linkage Consortium
published an analysis of a large number of BRCA2-
W. D. Foulkes
related breast cancers and showed that, compared with
controls, these cancers had (1) a higher score for tubule
formation (fewer tubules) (P = 0.0002), (2) a higher
proportion of the tumour perimeter with a continuous
pushing margin (P = 0.0001), and (3) a lower mitotic
count (P = 0.003) [25]. More recent immunohistochemical analyses by the same group showed that is difficult
to distinguish BRCA2-related from non-hereditary
breast cancer using ER, PR, p53 or erbB-2/HER2 [9],
and an analysis of relationship between tumour size and
the number of positive axillary lymph nodes also
indicates that BRCA2-related breast cancers are more
like non-hereditary cancers than are BRCA1-related
tumours [10]. Cyclin D1 is more likely to be expressed in
BRCA2-related breast cancer (and in sporadic breast
cancer) than in BRCA1-related breast cancer [7, 26], and
this could be a helpful marker in situations where
distinguishing which gene is involved is important. A
recent phylogenetic re-analysis of previously published
expression array data [7] demonstrated that a distinct
branch on the classification tree was occupied by
BRCA2-positive cancers: this was quite distinct from
the BRCA1-related cancer branch. Interestingly, socalled sporadic cancers appeared to be widely spread,
and were relatively distant from the path between the
BRCA1 and BRCA2 clusters [27].
Chemosensitivity: in vitro results (Table 1)
Some of the functions of BRCA1 and BRCA2 proteins, such as the role of BRCA1/2 in DNA repair [39]
or apoptosis [30, 40] could be directly involved in
response to cytotoxic agents. Mouse and human cell
lines deficient in BRCA1 or BRCA2 display an
increased sensitivity to agents causing double-strand
DNA breaks [41, 42]. In breast and ovarian cell lines,
over-expression of wild-type BRCA1 enhanced the
apoptotic response to a variety of stimuli, including
exposure to ionizing radiation and paclitaxel [30], and
absence of BRCA2 protein renders some cell lines
particularly sensitive to these agents as well as cisplatin
and camptothecin [33, 43]. Other studies demonstrated
this hypersensitivity for mitoxantrone, amsacrine, etoposide, doxorubicin and cisplatin with a subsequent
increased level of apoptosis, although results have not
been entirely consistent [34–36]. Differences in drug
sensitivity might be explained by differing levels of
down-stream effectors such as anti-apoptotic BCL-2
[44] or pro-apoptotic caspases in some hereditary
breast cancers. Indeed, more recent studies have
suggested that BRCA1 acts as a modulator of chemotherapy-induced apoptosis [29]. As noted previously,
there are different effects depending on which agents
are studied: the presence of BRCA1 induces a 10–1000fold increase in resistance to drugs that introduce DNA
double-strand breaks, such as etoposide and bleomycin, whereas increased sensitivity for spindle poisons
such as paclitaxel was noted. Very similar results were
seen in another study, but in this case, BRCA1 null
BRCA1/2, chemotherapy and outcome
Table 1. Summary of evidence for differential chemosensitivity in human breast/ovarian/pancreatic or murine cell lines with defined
BRCA1/2 levels
BRCA1 mutated
(loss of function)
Paclitaxel/ docetaxel
Ref. [28] only)
vinorelbine (Ref. [29]
apoptosis [29–31]
sensitivity [32, 34]
BRCA2 mutated
(loss of function)
apoptosis [29–32];
No effect [28]
sensitivity [33]
Similar effects seen
in one non-BRCA1/2
cancer cell line (Ref.
33). In Ref. 28,
mouse cells null for
p53 that were proficient or deficient for
Brca1 were used.
[28, 32, 34, 35]
sensitivity [33]
In Ref. 33, similar
effects seen in one
non- BRCA1/2
mutated ovarian
cancer cell line
(topo II poison)
(topo II poison)
sensitivity [36]
resistance [32]
sensitivity [32]
sensitivity [36]
sensitivity [32];
sensitivity [28]
(topo II poison)
resistance [36]
resistance [29]
Mitomycin c
resistance [37]
sensitivity [37]
5FU, anti-metabolites
No change [28]
(topo I poison)
sensitivity [28]
sensitivity [28]
sensitivity [36]
sensitivity [38]
NB checkpoint
mechanisms were
unaffected [38]
sensitivity [33]
Blank cells – no data identified, NB references in parentheses.
cells (HCC1937) were also insensitive to doxorubicin,
and this effect was reversed when wild-type BRCA1
was expressed [32]. There are two inferences from these
studies: (1) absence of BRCA1 results in an inverse of
the chemoresponsive phenotype seen when BRCA1 is
present; (2) More controversially, unlike the clinical
situation for most breast cancers, those occurring in
BRCA1 carriers are more likely to be resistant to
paclitaxel than to cisplatinum or etoposide. However,
in vitro and in vivo responses to chemotherapy may not
be closely correlated. To confuse matters, these results
with paclitaxel were contradicted by Zhou et al. who
found that the ovarian cancer cell line, SNU-251, that
contains a nonsense mutation in BRCA1, had increased
cellular sensitivity to ionizing radiation and paclitaxel
[31]. This sensitivity was reversed when wild-type
BRCA1 was expressed. This cell line is derived from
an ovarian, not a breast cancer, as in the previous
experiments [29]. It would be instructive to repeat the
experiments of Quinn et al. [29] using the same ovarian
cancer cell line. To further complicate the picture,
when compared with Brca1+/), p53)/) cells, murine
embryo fibroblasts lacking both Brca1 and p53 proteins had increased sensitivity to topotecan, doxorubicin, mitoxantrone, etoposide and platinum-containing
compounds, but no effect was seen on sensitivity to
5-fluorouracil, gemcitabine, docetaxel or paclitaxel [28].
As shown previously, much of the increased chemosensitivity was revealed by analysis of apoptotic pathways. Again, repeating these experiments using
inducible system and human cancer cell lines would
be of value, particularly as it known that DNA repair
systems, for example, differ between rodents and
humans [45]. To emphasize this difference, increased
mRNA levels of BRCA1 predicted a favourable
response to anthracycline-containing chemotherapy in
W. D. Foulkes
a study of 51 patients with breast cancer [46]: the
results from the experiments in mice described above
would have predicted the reverse effect [28] whereas
some previous experiments using the breast cancer line
HCC1937 are supportive of these findings [32].
Interestingly, mRNA levels of p53, erbB-2 and BRCA2
had no effect on response to the cyclophosphamide/
epirubicin regimens used [46].
Methylation of the promotor of BRCA1 could also
result in low mRNA levels [47, 48], and it is likely that
methylation-based gene silencing could underlie differences in response to chemotherapy in breast cancer, as
has been observed in glioma [49], where a better
response to carmustine was observed in individuals with
hypermethylation of the O6-methylguanine-DNA methyltransferase promoter than in those without hypermethylation. Interestingly, this hypermethylation is itself a
poor prognostic marker, and perhaps a similar poor
prognosis/good response combination of effects might
exist for mutations that prevent or limit accurate DNA
repair, such as BRCA1 or BRCA2, particularly when
treatments that cause double-strand breaks in DNA are
used. This interpretation is complicated by TP53 data:
here certain mutations seem to be both markers of poor
prognosis and poor response [50, 51]. On the other
hand, the main effect on chemo-responsiveness in cancer
cells with TP53 mutations may not operate through the
DNA repair pathway, and the complex effects of loss of
TP53 on cellular functions may obscure pathwayspecific differences. A central role for RAD51 in DNA
repair processes has been noted, but the significance of
the reported association between RAD51 expression
levels and resistance to chemotherapy remains uncertain, particularly as studies provide conflicting data [52].
Interestingly, several studies have suggested that single
nucleotide polymorphisms in RAD51 can modify cancer
risk in BRCA2 (but not BRCA1) mutation carriers
Forcing cells to repair artificially created doublestrand breaks by the use of homologous recombination
(HR) could lead to cell death in cells that lack intact HR
pathways. The premise that BRCA1 and BRCA2 null
cells might be especially prone to respond in this fashion
was borne out by two recent studies [56,57], that used an
inhibitor of the enzyme, poly (ADP-ribose) polymerase
(PARP). In these studies, selective inhibitors of PARP1
were tested in mouse and human BRCA1 and BRCA2
null cell lines. BRCA1 or BRCA2 dysfunction profoundly sensitized cells to the inhibition of PARP
enzymatic activity. This resulted in chromosomal instability, followed by cell cycle arrest and finally cell
death by apoptosis. This very exciting laboratory work
suggests that clinical studies focused on the targeted
inhibition of particular DNA repair pathways could be
a new and effective way to treat cancers arising in
BRCA1 or BRCA2 mutation carriers.
Chemosensitivity: in vivo results (Table 2)
There have been no prospective randomized controlled
trials of different chemotherapeutic regimens in BRCA1/
2 carriers. The closest to this ideal has been provided by
retrospective analysis of completed studies where treatment was not based on mutation status, but was
randomly assigned.
A differential response to neo-adjuvant chemotherapy for breast cancer on the basis of germ-line BRCA1/2
mutation status may exist. After 3 or 4 cycles of neoadjuvant chemotherapy, a complete clinical response
(cCR) was recorded in 10 of 11 BRCA1/2 carriers
compared with 8 of 27 non-carriers (P = 0.0009) [58].
Notably, 4 (2 BRCA1 carriers and 2 BRCA2 carriers) of
9 evaluable BRCA1/2 carriers had no residual tumour in
the breast and the axillary lymph nodes (a complete
pathological response, or pCR), whereas only one case
of pCR (4%) was noted among the non-carriers
(P = 0.009). When the cases were matched 1:1 to
controls on precise TNM stage, the significance of the
effect of mutation status on complete clinical response
rate was slightly less marked. Overall, in this very small
retrospective study, BRCA1/2 carriers demonstrated a
better clinical response rate to neo-adjuvant chemotherapy than did non-carriers. Importantly, the clinical and
pathological responses to adjuvant treatment observed
in BRCA1/2 non-carriers were concordant with what
has been reported previously, and such responses are
not stage-dependent [65].
Support for this observation was provided by a case
report from Warner and colleagues [59], who treated a
49-year old woman with neo-adjuvant anthracycline-
Table 2. Summary of evidence for differential response to chemotherapeutic agents in BRCA1- and BRCA2-related breast and ovarian cancers: clinical studies
Wt BRCA1 or
high levels of wt BRCA1
BRCA1 mutation or
loss of function
BRCA2 mutation or
loss of function
Increased sensitivity [46]
Increased sensitivity
No effect of BRCA2
mRNA levels on
response [46]
Increased sensitivity
Increased sensitivity
Breast cancer studied:
small studies, retrospective cohort studies and
case reports only
Ovarian cancer studied:
no differences between
BRCA1/2, chemotherapy and outcome
containing chemotherapy because of a 3 cm invasive
ductal breast carcinoma, associated with an ipsilateral
3.5 cm axillary mass. By the middle of the second cycle,
no masses could be identified clinically, by magnetic
resonance imaging or by mammography. She was
subsequently identified as a carrier of an Ashkenazi
Jewish founder mutation in BRCA1. At definitive
surgery, the total mastectomy specimen was free of
These findings have been indirectly supported by a
recent study that showed that ‘‘basal’’(i.e BRCA1-like)
and HER2- positive cancers were the only types of
breast cancer which responded well to neo-adjuvant
chemotherapy (66). In both groups, 45% had a pCR,
exactly the same numbers are seen in the study of
Chappuis et al [58], suggesting strongly that the basal
pathway is a key factor in the response observed by that
Another study, also from M.D. Anderson, showed
that low levels of BCL-2 are associated with a good
response to adjuvant chemotherapy [67], but was not
associated with a better long-term survival (BCL-2
positive (56%) vs BCL-2 negative (48%), P = 0.58)
Notably, BRCA1-related breast cancers often exhibit
low levels of BCL-2 (44). Other basal-associated
oncoproteins such a aB-crystallin are also associated
with a poor prognosis [68] and the presence of a woundresponse signature, over-represented in basal breast
cancers, is also seen in breast cancers that have an
adverse outcome [69].
The apparent paradox is that despite this excellent
initial response to chemotherapy (as demonstrated by
high pCR rates in basal and BRCA1-related breast
cancer), cancer is more likely to recur early in basalrelated than in other types of breast cancer (and in our
data set, this is true for BRCA1-related cancers too). It
appears that although basal breast cancers may respond
well to adjuvant chemotherapy [70], response at time of
first relapse is poor [71], and this could, in part, explain
the poor overall prognosis. Well controlled studies of
both basal and non-basal forms of BRCA1-related
cancer are required to establish the independence of
the initial response to chemotherapy in BRCA1 mutation carriers from the basal phenotype. Furthermore,
the unsustained nature of the response, in at least some
studies, suggests that urgent attempts to identify
biological treatments are justified.
The single historical cohort study including a multivariable analysis showed that it is only among affected
women not receiving chemotherapy that the presence of a
BRCA1 mutation is associated with an adverse prognosis
[58]. This provides supporting evidence for a role for
BRCA1 in determining response to chemotherapy, but
other interpretations of the data are possible, and given
then lack of randomization, it is risky to infer too much
from such data. The only other study, where the data
were not divided by germ-line BRCA1/2 mutation status,
but by mRNA levels in the cancers [46], found that, in
contrast to the above studies, that increased mRNA
levels of BRCA1 predicted a favourable response to
anthracycline-containing chemotherapy. As discussed in
the previous section, there are conflicting data from cell
line experiments [28, 32]
Several in vitro studies showed increased sensitivity of
some ovarian cell lines carrying mutated BRCA1 alleles
to various chemotherapeutic agents [30]. Supporting
these data, the unbiased historical cohort study by Boyd
and colleagues demonstrated that ovarian cancer among
Ashkenazi Jewish BRCA1/2 mutation carriers had a
better outcome when compared with ovarian cancer in
Ashkenazi Jewish non-carriers [61]. Interestingly,
although the hereditary and sporadic cancers presented
with pathological and treatment (cisplatin-based regimens) characteristics that were remarkably similar, the
BRCA1/2-associated cancers were more likely to be
optimally cytoreduced at primary surgery and hereditary cases had a significantly longer disease-free interval
following primary chemotherapy (P = 0.001). These
data are compatible with the hypothesis of a more
favourable response to chemotherapy among hereditary
ovarian cancer cases [61], and have been confirmed by
other studies [62–64], although survival differences
between familial and non-familial ovarian cancer (without referring to mutation data) are less apparent
[72–74]. There do not appear to be important survival
differences between BRCA1 and BRCA2 mutation
The Fanconi-BRCA ovarian cancer connection
The mechanism by which platinum-based drugs produce their effect on ovarian cancer is of substantial
interest. It has been observed that Fanconi anemia
(FA) cells have increased chromosome breakage and
radial formation after cellular exposure to mitomycin
C (MMC) [75]. Murine cells lacking Brca1 or Brca2
can also develop a Fanconi anemia-like phenotype,
particularly after MMC exposure [37, 38], and
FANCD1 has recently been found to be BRCA2 [76].
The BRCA1, BRCA2 and FA gene products interact
intimately [77], and normal functioning of this pathway
is required for a normal cellular response to DNA
cross-linking drugs such as cisplatinum. Recently, it
has been suggested that about one-fifth of primary
ovarian carcinomas have some disruption of the
FANC-BRCA pathway, resulting from biallelic methylation of FANCF [78]. The BRCA1/2 mutation status
of the women was not reported. Reversion in one
ovarian cancer cell line to cisplatinum resistance was
associated with demethylation of FANCF. Therefore
cisplatinum sensitivity could, in part, be explained by
somatic inactivation of the FANC-BRCA pathway.
Hypermethylation of the BRCA1 (and to a lesser
extent, BRCA2) promoter is seen in non-hereditary
ovarian cancers [48, 79], so it is plausible that the
mechanism of cisplatinum sensitivity reported by
Taniguchi et al. [78] could have a wider significance
if methylation of BRCA1 could functionally substitute
for methylation of FANCF. Could a similar effect be
present in BRCA1/2-related breast cancer?
Prognosis in hereditary breast cancer
This subject has been extensively reviewed elsewhere and
has been alluded to in the sections above. Suffice it to
say that most studies find that the prognosis for
BRCA1-related breast cancer is either similar or worse
than age-matched controls. For BRCA2, there are less
data, but no substantial differences in outcome have
emerged [3, 80, 81]. Non-BRCA1/2-hereditary breast
cancers have a less aggressive profile than BRCA1/2related cancers [82], but the prognostic implication of
this has not been studied, for the obvious reason that the
genes are not known, and no one single gene or
mutation, apart perhaps for CHEK2:1100delC in Finland or the Netherlands, has attained a sufficient
frequency to permit such an analysis [83]. Surprisingly,
other breast cancer susceptibility genes, such as TP53,
PTEN and STK11 have not been subjected to survival
analyses [81].
Clinical implications and future directions
Identifying germ-line BRCA1/2 mutations before definitive treatment (whether surgical, medical or radiotherapeutic) is beginning to become part of the management
of women with breast cancer. Certainly, mutation status
influences surgical choices: women with mutations are
much more likely to undergo bilateral mastectomy at
primary diagnosis than are non-carriers [84], and this
will in turn influence decisions regarding the use of
radiotherapy. As yet, there is only a sense that knowledge of mutation status might influence the decision to
administer chemotherapy to women with small, nodenegative, high-grade breast cancers, insofar as those
with BRCA1 mutations may be more likely to benefit
than those without [3]. But since many such women
probably will receive chemotherapy anyway, this is a
marginal contribution. What is more important is if
certain regimens are found to be more effective than
others in BRCA1/2 carriers. The burning question at the
moment is whether platinum-containing compounds
will be more effective than taxanes in breast cancer.
This conjecture is supported by the literature discussed
above. A trial of this nature, in metastatic breast cancer,
has just commenced in the U.K. with plans for worldwide enrollment. For anthracyclines, the data are much
less clear: most clinical data showing hints of increased
responses in BRCA1/2 carriers are based on anthracycline-containing regimens, but the laboratory data are
much less encouraging, and the only way to satisfactorily answer these questions will be randomized clinical
trials in affected BRCA1/2 mutation carriers.
With increasing availability of gene expression data,
it may be that clinicians will move straight to the
somatic data, without the need to consider germ-line
mutation status, and this may obviate the need for such
W. D. Foulkes
studies in primary breast cancer. Nevertheless, particularly in settings where suitable tissue is not available or
hard to access (for example in recurrent disease),
knowledge of mutation status could be of value in
deciding on the ‘best bet’ for first-line chemotherapy.
Notably, the BRCA1-associated basal phenotype seen
in primary breast cancers appears to be stable over time,
and metastases developing months or years later possess
a very similar gene expression signature [85], suggesting
an important role for BRCA1 in determining the gene
expression profiles of distant metastases.
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