Keywords breast cancer -
BRCA1/2 diagnostics - therapy planning - PARP inhibitors - talazoparib - olaparib
Introduction
Breast cancer is a heterogeneous disease which requires individualized targeted therapy
concepts. Biologically distinct subtypes correlate with genetic variants which are
not just relevant for estimating the risk of developing breast cancer but are also
increasingly predictive for drug therapy strategies. Pathogenic variants of the breast
cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2 ) are mainly responsible for a predisposition to breast cancer and also the most important
predictive factor for the patient’s response to a targeted therapy with poly ADP-ribose
polymerase (PARP) inhibitors [1 ]
[2 ]
[3 ].
The onus is on the treating oncologists and gynecologists to know when genetic testing
is indicated and to offer and arrange for BRCA1/2 germline testing when indicated.
This article focuses on the practical aspects of implementing BRCA1/2 germline testing in patients with breast cancer to ensure the best possible therapy.
Detection of a pathogenic BRCA1/2 germline mutation is decisive for therapy with a PARP inhibitor (PARPi), and treatment
with a PARPi is now no longer limited to advanced disease but, based on the recent
expansion of the regulatory approval for PARPi, is also clinically relevant for early-stage
disease [4 ]
[5 ].
Hereditary Breast Cancer
Significance of risk genes
The lifetime risk of developing breast cancer for women is about 13%. About 1% of
all new cases with disease are men [6 ]
[7 ]. The lifetime risk increases if a pathogenic germline mutation of the high-risk
genes BRCA1 or BRCA2 is present and is around 40–60%. PALB2, CDH1, PTEN, TP53 and STK11 are also associated with a high risk of developing breast cancer and ATM , CHEK2 , BARD1 , RAD51C and RAD51D with a moderate risk of breast cancer [1 ]
[8 ]
[9 ]
[10 ].
Most mutations of established breast cancer predisposition genes affect BRCA1/2 . It is estimated that about 5% of all patients with breast cancer have a pathogenic
BRCA1/2 germline mutation [8 ]
[11 ]
[12 ]
[13 ]. In the heterogeneous group of breast carcinomas, the mutation frequency varies
according to subtype. In general, pathogenic mutations in BRCA1/2 result in a more aggressive pathology (triple-negative subtype, higher grading).
The strongest association is between BRCA1 and triple-negative breast cancer (TNBC). As hormone receptor-positive (HR+) breast
cancer, which is also negative for human epidermal growth factor receptor 2 (HER2−),
is by far the most common subtype, numerically the majority of mutation carriers have
an HR-positive pathology [11 ]
[14 ]. Even though the cumulative familial occurrence of breast and/or ovarian cancer
and/or early-age onset of disease are characteristic for hereditary breast cancers
and the frequency of BRCA1/2 mutations is greatest for TNBC, clinical parameters such as familial history, age,
or tumor type are only associated with some of the mutations.
Special features in the treatment of tumors with BRCA1/2 mutation
Many predisposition genes for breast and ovarian cancer play a role in homologous
recombination, a key function for the repair of DNA double-strand breaks. Blocking
DNA single-strand breaks through inhibition of PARP1 enzymes results in an accumulation
of double-strand breaks which, in cells with homologous recombination deficiency,
can only be repaired by less efficient and error-prone non-homologous recombination
(non-homologous end joining, NHEJ). The biallelic inactivation of BRCA1/2 genes in tumor cells and concurrent inhibition of PARP1 leads to the loss of genomic
integrity of tumor cells resulting in cell death (synthetic lethality) [15 ]
[16 ].
Relevance of BRCA1/2 Testing in Healthy Populations and Populations with Cancer
Relevance of BRCA1/2 Testing in Healthy Populations and Populations with Cancer
Identification of BRCA1/2 germline mutations to estimate the risk of developing breast and/or ovarian cancer
A molecular diagnostic workup to identify mutations in the BRCA1/2 genes offers the opportunity to estimate the risk of developing breast and/or ovarian
cancer and includes, in addition to testing patients who have already developed cancer,
the testing of healthy persons, particularly family members of patients with confirmed
gene mutations, to detect genetic risks early on. Proof of pathogenic BRCA1/2 variants permits intensified screening to be carried out of persons who have not
yet developed disease and helps to detect emerging carcinomas in their very early
stages (secondary prevention). Preventive measures such as surgery or drugs can also
be used (primary prevention). For patients who have already developed cancer, testing
offers the possibility of a more intensive follow-up and of risk-reducing interventions
(surgery or drugs) because of the increased risk of secondary disease (contralateral
breast and/or ovarian cancer) [1 ].
BRCA1/2 germline mutations as a predictive factor for therapy response
BRCA1/2 mutations influence the response to certain drugs and identifying them is therefore
vitally important when planning individualized therapy concepts [1 ]
[2 ]
[3 ]
[17 ]. Identification of a BRCA1/2 germline mutation means that treatment with PARPi is possible, which contributes
to longer term control of the disease. Since 2019, breast cancer patients with confirmed
pathogenic BRCA1/2 germline mutations can benefit from olaparib or talazoparib monotherapy to treat
HER2-negative advanced disease, and, since August 2022, they may also benefit from
(post-neo)adjuvant therapy with olaparib to treat early-stage HER2-negative disease
with a high risk of recurrence [4 ]
[5 ]. Moreover, BRCA1/2 mutations are predictive of chemotherapy response in the neoadjuvant setting [18 ]
[19 ]
[20 ]. A higher sensitivity to platinum has also been reported for persons with BRCA1/2 germline mutations and advanced triple-negative disease [21 ], although the addition of platinum agents is now standard in the treatment of triple-negative
breast cancers in the neoadjuvant setting [22 ]
[23 ].
Data on routine clinical care prior to the approval of PARPi to treat breast cancer
show the need for targeted and well-tolerated therapies for patients with BRCA1/2 mutated breast cancer. Despite the option of endocrine therapy, women with HR-positive
disease had chemotherapy significantly more often in the metastatic setting if they
had a BRCA1/2 mutation. Adverse events were more common and the quality of life of BRCA1/2 mutation carriers was lower compared to patients without BRCA1/2 mutations [24 ]
[25 ]
[26 ].
Indications for PARP Inhibitors
Indications for PARP Inhibitors
The first PARPi, olaparib, was approved for use in Europe by the European Commission
in December 2014 for the maintenance treatment of patients with relapsed ovarian cancer
who had responded to previous platinum-based chemotherapy. This was followed by regulatory
approval of niraparib and rucaparib for the same indication. Since 2019, olaparib
as well as talazoparib have also been approved to treat HER2-negative locally advanced
or metastatic breast cancer in patients with BRCA1/2 germline mutations. The regulatory approval of olaparib was recently expanded (EU:
August 2022, USA: March 2022) to include patients with early-stage HER2-negative breast
cancer. More information on the indications for using PARPi is given in [Table 1 ].
Table 1
Regulatory approval status of PARP inhibitors in Europe.
For more details on indications, please refer to the respective specialist information.
* Positive status for homologous recombination deficiency (HRD) defined by BRCA1/2 mutation and/or genomic instability.
** Rucaparib should no longer be used as monotherapy to treat patients with (germline
and/or somatic) BRCA1/2 mutated advanced ovarian cancer who have been treated with two or more prior lines
of platinum-based CT and are unable to tolerate further platinum-based CT. The randomized
controlled clinical post-approval study CO-338–043 (ARIEL4) reported adverse effects
of rucaparib on overall survival (OS) compared to CT controls (HR 1.31; 95% CI: 1.00–1.73),
which led to the issue of a Direct Healthcare Professional Communication (in Germany:
Rote-Hand-Brief) [27 ].
HER2-negative breast cancer
Early-stage disease
Monotherapy or in combination with endocrine therapy for the adjuvant treatment following
neoadjuvant or adjuvant chemotherapy (CT) to treat patients with a high risk of recurrence
Olaparib for patients with BRCA1/2 germline mutations
Advanced-stage disease
Monotherapy
Olaparib and talazoparib for patients with BRCA1/2 germline mutations
Advanced ovarian cancer
First-line therapy
First-line maintenance therapy (FIGO III/IV) for patients who have responded to platinum-based
CT
Olaparib for patients with BRCA1/2 mutations (germline and/or somatic); combined with bevacizumab for patients who are
HRD-positive*
Niraparib independent of BRCA1/2 status
Recurrence therapy**
Maintenance therapy for patients with platinum-sensitive recurrence who have responded
to platinum-based CT
Olaparib, niraparib and rucaparib independent of BRCA1/2 s tatus
Metastatic pancreatic adenocarcinoma
Maintenance therapy for patients who did not experience progression after at least
16 weeks of first-line platinum-based CT
Olaparib for BRCA1/2 germline mutation
Metastatic castration-resistant prostate cancer
Monotherapy for patients who have progressed following prior therapy with a new hormonal
agent
Olaparib for patients with BRCA1/2 mutation (germline and/or somatic)
Approval for PARP Inhibitors to Treat Advanced and Early-stage Breast Cancer in Patients
with BRCA1/2 Germline Mutations: OlympiAD, EMBRACA and OlympiA Trials
Approval for PARP Inhibitors to Treat Advanced and Early-stage Breast Cancer in Patients
with BRCA1/2 Germline Mutations: OlympiAD, EMBRACA and OlympiA Trials
Efficacy
For the PARPi substance class, monotherapy with olaparib (OlympiAD) or talazoparib
(EMBRACA) resulted in a significantly longer progression-free survival (PFS) of about
three months compared to standard chemotherapy in patients with HER2-negative locally
advanced or metastatic breast cancer with confirmed BRCA1/2 germline mutations. This corresponds to a reduction of the risk of progression of
more than 40%. The response rate in the group treated with a PARPi was about twice
as high as in the group which received standard chemotherapy ([Table 2 ]). The time to the onset of a response for olaparib or talazoparib was comparable
to that for chemotherapy [28 ]
[29 ]. The benefit of olaparib or talazoparib was independent of the site of metastasis
and appeared to be consistent in patients with visceral as well as brain/CNS metastases
[29 ]
[30 ]. In the extended follow-up period of the OlympiAD trial, olaparib was not associated
with a statistically significant improvement in overall survival (median OS: 19.3
vs. 17.1 months; HR 0.90; 95% CI: 0.66–1.23; p = 0.513). One possible OS benefit of
olaparib vs. chemotherapy only became apparent when olaparib was administered as first-line
therapy (median OS: 22.6 vs. 14.7 months; HR 0.51; 95% CI: 0.29–0.90; p = 0.02) [31 ].
Table 2
OlympiAD and EMBRACA trials leading to the approval of PARP inhibitors to treat HER2-negative
locally advanced or metastatic breast cancer in patients with confirmed BRCA1/2 germline mutations.
OlympiAD (olaparib vs. CT)
EMBRACA (talazoparib vs. CT)
CT = standard chemotherapy; HR = hazard ratio; CI = confidence interval; PFS = progression-free
survival
Median PFS
7.0 vs. 4.2 months
8.6 vs. 5.6 months
HR (95% CI)
0.58 (0.43–0.80); p < 0.001
0.54 (0.41–0.71); p < 0.001
Response rate
59.9% vs. 28.8%
62.6% vs. 27.2%
In the (post-neo)adjuvant setting, olaparib therapy resulted in a significant prolongation
of invasive disease-free survival (iDFS) and distant disease-free survival (dDFS)
as well as – according to the new 4-year data of the OlympiA trial – better overall
survival (OS) in patients with early-stage HER2-negative breast cancer with a high
risk of recurrence and confirmed BRCA1/2 germline mutations compared to placebo. Olaparib therapy significantly reduced the
risk of an iDFS event by 42% and the risk of death by 32% ([Fig. 1 ]). Subgroup analyses (according to hormone receptor status, previous platinum-based
therapy yes vs. no, previous chemotherapy adjuvant vs. neoadjuvant) showed no evidence
for heterogeneity, even though the number of deaths was low in some of the subgroups.
CNS recurrence was the first iDFS event for 2.4% of patients in the olaparib group
vs. 3.9% in the placebo group [32 ]
[33 ]
[34 ]. [Fig. 2 ] shows the study design of the OlympiA trial.
Fig. 1 OlympiA trial leading to the approval of olaparib to treat early-stage HER2-negative
breast cancer with a high risk of recurrence in patients with confirmed BRCA1/2 germline mutations (modified from [33 ]
[35 ]): significant improvement of the 3-year iDFS rate (p < 0.001) (a ) and the 4-year OS rate (p = 0.009) (b ) after 1 year of (post-neo)adjuvant therapy with olaparib compared to placebo after
(neo)adjuvant chemotherapy. HR = hazard ratio; iDFS = invasive disease-free survival;
CI = confidence interval; OS = overall survival; * A 98.5% CI was used, as p < 0.015
was necessary for statistical significance.
Fig. 2 OlympiA patient cohort and study design. CPS + EG: prognostic score based on clinical
staging prior to treatment (CS) and after neoadjuvant chemotherapy (PS), estrogen
receptor status (E) and grading (G) to estimate the prognosis after neoadjuvant chemotherapy.
* Stratified according to hormone receptor status (HR+/HER2− or TNBC), timing of previous
CT (neoadjuvant or adjuvant) and use of previous platinum-based therapy for breast
cancer (yes or no). Bisphosphonates and endocrine therapy in both treatment arms as
adjuvant therapy according to institutional guidelines.
The Breast Committee of the German Working Group for Gynecological Oncology (AGO)
has therefore recommended olaparib for use as (post-neo)adjuvant treatment even prior
to its approval by the European Commission for all HR+/HER2− and TNBC patients with
BRCA1/2 germline mutations based on the population in the OlympiA trial (for further information
see chapter on Guidelines and Recommendations on Molecular Diagnostics and Therapy ) [17 ].
Quality of life
Efficacy benefits reported for PARPi include maintaining patients’ quality of life.
In contrast to chemotherapy, patients’ quality of life in an advanced therapy setting
improved with olaparib or talazoparib. Only gastrointestinal complaints, especially
nausea and vomiting, were perceived as equally difficult or, particularly in the early
stages of treatment, more burdensome under PARPi therapy compared to chemotherapy,
which corresponds to the adverse events profile of PARPi. The study participants felt
that other symptoms, particularly measured on the fatigue, pain, and appetite loss
subscales, were less severe under PARPi therapy than under chemotherapy [36 ]
[37 ]. The impact on quality of life based on both adverse events and the therapeutic
effect is thus significantly lower with a PARPi versus chemotherapy.
Quality of life remained largely unchanged during (post-neo)adjuvant olaparib therapy
in the early-stage therapy setting. Although there was a statistically significant
worsening of fatigue symptoms during olaparib therapy, the changes to FACIT Fatigue
scores were below the clinically meaningful difference of 3 points [38 ]. A statistically and clinically significant but small worsening was shown for the
symptom subscales Nausea and Vomiting during therapy [39 ]. The symptoms improved again directly after completion of therapy, meaning that
the additional (post-neo)adjuvant therapy with olaparib did not meaningfully affect
recovery after standard (neo)adjuvant treatment [40 ].
Routine Use of PARP Inhibitors to Treat Advanced Breast Cancer
Routine Use of PARP Inhibitors to Treat Advanced Breast Cancer
Clinical routine data and real-world data have confirmed the efficacy and tolerability
of olaparib and talazoparib in patients with HER2-negative advanced breast cancer
and BRCA1/2 germline mutations. In the phase IIIb LUCY trial, the median duration of olaparib
treatment was 8 months. The median PFS was 8.2 months and the median OS was 24.9 months
(27.4 months when olaparib was administered as first-line therapy vs. 22.7 months
for later lines). Therapy discontinuation because of adverse events was rare (4.3%)
[41 ]. The initial results of the phase IV ViTAL trial report a median duration of talazoparib
treatment of 9 months as well as a low discontinuation rate due to adverse events
(8.0%) [42 ].
Guidelines and Recommendations on Molecular Diagnostics and Therapy
Guidelines and Recommendations on Molecular Diagnostics and Therapy
In the 2022 update of the recommendations for the diagnosis and treatment of patients
with early and advanced breast cancer, the Breast Committee of the German Working
Group for Gynecological Oncology (AGO) once again gave the highest level of recommendation
to carrying out BRCA1/2 gene testing in:
every case where it would be therapeutically relevant (e.g., PARPi), and
every patient with a possible hereditary predisposition for breast and/or ovarian
cancer based on familial history and the patient’s own medical history (including
TNBC before the patient’s 60th birthday, and development of ovarian cancer) according
to the checklist of the German Cancer Society [43 ]
Moreover, patients with a positive familial history and a suspicion of hereditary
breast/ovarian cancer should receive testing for additional risk genes (e.g., gene
panels, including BRCA1/2 ) [1 ].
Use of a PARPi (olaparib or talazoparib) was again recommended for patients with confirmed
BRCA1/2 germline mutations and (HER2-negative) metastatic disease. In addition, (post-neo)adjuvant
use of olaparib was recommended for the first time (since April 2022) for patients
with confirmed BRCA1/2 germline mutations and (HER2-negative) early-stage disease who have a high risk of
recurrence after completion of standard treatment – even before the relevant expanded
regulatory approval was granted [44 ].
Testing to allow therapy planning is therefore recommended, irrespective of the assessment
of familial risk, for all patients who are eligible for PARPi therapy in accordance
with the appropriate regulatory approval. This includes testing to plan:
systemic therapy with a PARPi (olaparib, talazoparib) to treat adult patients with
HER2-negative locally advanced or metastatic breast cancer if indicated, and
adjuvant therapy with olaparib after (neo)adjuvant chemotherapy to treat adult patients
with early-stage HER2-negative breast cancer and a high risk of recurrence
If treatment is curative and chemotherapy is indicated, neoadjuvant chemotherapy should
be preferred, particularly in patients with triple-negative disease. In patients with
BRCA1/2 germline mutations, post-neoadjuvant treatment with olaparib is recommended if indicated,
where appropriate with the addition of endocrine therapy (HR+) [17 ].
The ESMO guideline on metastatic breast cancer also recommends therapy planning based
on BRCA1/2 germline status in patients with HER2-negative disease. The most recent research
results for early-stage therapy have, however, not yet been included in the ESMO guideline
on early-stage breast cancer [45 ]
[46 ]. The updated breast cancer guidelines of the National Comprehensive Cancer Network (NCCN) also support testing for therapy planning in cases with advanced disease and,
for the first time (since December 2021), in cases with early-stage breast cancer
and a high risk of recurrence [3 ].
Outpatient BRCA1/2 Germline Testing
Outpatient BRCA1/2 Germline Testing
Requirements for testing
Blood samples are needed to detect BRCA1/2 germline mutations as these mutations are present in all eukaryotic cells, whereas
somatic mutations are only present in tumor cells and are therefore detected in tumor
tissue (s. also [Table 1 ] on the regulatory approval status of PARPi with regards to BRCA1/2 mutation status). In Germany, genetic analysis of a germline mutation is subject
to the provisions of the German Genetic Diagnostics Act (GenDG, Sec. 2) which requires
that the person who will undergo testing is given detailed information about the procedure
as well as an analysis of their own/their familial medical history and provides written
consent (§ 8 + 9). All registered physicians are permitted to arrange diagnostic testing
for therapy planning. Treating physicians with the appropriate qualifications decide
on the indications for testing at their own discretion. However, physicians who arrange
to carry out predictive diagnostics in healthy at-risk persons must have a qualification
in human genetics and must offer genetic counselling before and after testing (§ 7 + 10)
[47 ]. The pathway to arrange for germline diagnostics in order to plan the therapy of
persons who have developed disease or persons with a suspicion of hereditary breast
cancer is shown in [Fig. 3 ].
Fig. 3 Arranging and implementing BRCA1/2 germline diagnostics in Germany: BRCA1/2 germline diagnostics for therapy planning is based on the regulatory approval of
PARP inhibitors to treat HER2-negative breast cancer in cases with advanced or early-stage
disease and can be arranged by the treating physicians for all patients for whom such
treatment would be appropriate. If there is a suspicion that the patient may have
a familial predisposition, multi-gene panel testing (including BRCA1/2 diagnostics) instead of single tests may already be carried out at diagnosis. After
the person who will be tested has been provided with the necessary information and
has given their informed consent in accordance with the Genetic Diagnostics Act (GenDG),
the blood sample is either sent to an approved human genetics laboratory or to a laboratory
of a Consortium center together with a letter of referral ordering the laboratory
tests (No. 10 sample referral letter). Since January 1st, 2022, testing in patients
with early-stage disease is also reimbursed through the einheitlicher Bewertungsmaßstab (EBM; a uniform assessment standard for doctors’ fees used in Germany). Billing is
done by the laboratory which carries out the testing.
Communicating the findings
Test results should be available soon after initiation of the test. A German study
on diagnostic testing found, however, that it took four weeks on average until the
test results were available. Only 24% of the physicians received a test result within
two weeks [48 ]. The processes in the majority of laboratories clearly require optimization. The
clinically relevant sequence variants are classified as pathogenic, likely pathogenic,
or not pathogenic (or uncertain for variants of uncertain clinical significance) [49 ]. If a (likely) pathogenic variant is detected, the tested patient must be offered
genetic counselling by physicians with the appropriate qualifications (§ 10 GenDG)
[47 ].
Testing Behavior
Routine clinical care data show that, depending on the respective country, testing
rates still vary greatly despite widespread clear recommendations in national and
international guidelines supporting genetic testing for BRCA1/2 in cases with possible hereditary predisposition and cases who have been diagnosed
with HER2-negative breast cancer and metastatic disease irrespective of their familial
history. The testing rates in routine clinical practice in most countries are low,
even when PARPi are available. Studies on BRCA1/2 testing rates in Europe and the USA before and after regulatory approval of PARPi
for patients with HER2-negative advanced breast cancer show that testing rates in
this setting were declining between 2015 and 2017, particularly for cases with HR-positive
disease. This is possibly due to the availability of CDK4/6 inhibitors, which are
used independent of BRCA status. As PARPi became available for patients with advanced breast cancer, testing
rates increased again in 2019/2020, both for cases with triple-negative disease and
cases with HR-positive disease, but rates were still too low, especially for patients
with HR-positive disease and in Europe, where testing rates amounted to just 37% ([Fig. 4 ]). Patient age also affected testing rates: older women were tested significantly
less often, and this was the case whether they had triple-negative disease or HR-positive
disease. Testing rates were significantly lower for all age groups with HR-positive
disease; in 2019/2020, the testing rates for women aged ≥ 65 years were only 25% compared
to 64% for TNBC ([Fig. 5 ]). Testing rates were also affected by patients’ familial history: women with a positive
familial history were tested significantly more often, irrespective of the subtype
(whether it was triple-negative disease or HR-positive disease) and the patient’s
age (across all age
groups) [50 ]
[51 ].
Fig. 4
BRCA1/2 testing rates according to region, hormone receptor status, and year for women with
HER2-negative advanced breast cancer (modified from [50 ]
[51 ]): the BRCA1/2 testing rates for women with HER2-negative advanced breast cancer declined between
2015 and 2017 both in Europe (EU4: Germany, France, Italy, Spain) and the USA for
HR-positive disease. When PARPi became available, testing rates increased again in
2019/2020 (both for cases with triple-negative disease and cases with HR-positive
disease) but were still low, especially in patients with positive HR status and patients
living in Europe. The data on testing rates was collected as part of three surveys
carried out at different times (February to May 2015, March to July 2017 and September
2019 to April 2020). To obtain the information, oncologists consecutively extracted
the relevant data from medical charts for the next 8–10 patients with HER2-negative
advanced breast cancer. BRCA1/2 mutation carriers were overrepresented in the 2019/2020 survey.
Fig. 5
BRCA1/2 testing rates according to hormone receptor status, year, and age for women with
HER2-negative advanced breast cancer in Europe (modified from [51 ]): BRCA1/2 testing rates for women with HER2-negative advanced breast cancer before (2015 and
2017) and after (2019/2020) regulatory approval of PARPi in Europe (EU4: Germany,
France, Italy, Spain) were strongly affected by patient age. Older women were tested
significantly less often, irrespective of whether they had triple-negative disease
or HR-positive disease. Women with HR-positive disease were less likely to be tested
across all age groups than patients with TNBC. For details on how the data on testing
rates was collected, see the caption to [Fig. 4 ].
A survey carried out in 2019/2020 on implementing BRCA1/2 germline testing for patients with HER2-negative advanced breast cancer in Europe
(EU4), the USA, und Israel revealed significant regional differences. Almost all (97%)
of the surveyed oncologists in Israel stated that they carried out BRCA1/2 germline testing, demonstrating a greater willingness to carry out testing in high-risk
groups [52 ]; in the USA, the percentage was 45% and in Europe it was only 26%. In Israel, 90%
of surveyed oncologists tested all patients with HER2-negative advanced breast cancer;
23% did so in the USA and only 5% in Europe. In the academic setting, testing was
carried out more frequently across all regions. Testing was also carried out more
often if PARPi were easily available [53 ].
According to a German study from 2019/2020, access to both BRCA1/2 germline testing and PARPi therapy is considered feasible in the outpatient oncology
setting. The majority (84%) of surveyed oncologists rated access to testing as very
good, good, or satisfactory. The majority was aware of the therapeutic relevance of
BRCA1/2 germline testing, although 22% were not sufficiently aware of its importance. The
surveyed oncologists also stated that a positive familial history continued to be
the most important factor influencing their decision to perform BRCA1/2 germline testing for patients with advanced disease, followed by guidelines, the
presence of triple-negative disease, and patient age at onset of disease. Despite
the available infrastructure and an awareness of the relevance of guidelines, only
30% of surveyed oncologists carried out genetic testing in patients with advanced
HR+/HER2− disease if the patient had no positive familial history; in cases with advanced
triple-negative disease the rate was 92% ([Fig. 6 ]) [48 ].
Fig. 6 Testing rates for BRCA1/2 germline testing according to receptor status and familial history in Germany (modified
from [48 ]): the results of an online survey carried out between October 2019 and February
2020 of BRCA1/2 germline testing (gBRCA1/2 testing) in patients with advanced breast cancer show that the percentage of surveyed
licensed oncologists (n = 50) who carry out testing in patients with HR-positive disease
and a negative familial history is still very low. The main reasons cited by respondents
why they did not test this patient population was the availability of other therapeutic
options, followed by reimbursement difficulties.
Conclusion
The identification of molecular and predictive parameters in patients with breast
cancer allows the probability of the effect of a given therapy to be predicted. Pathogenic
BRCA1/2 mutations are not only associated with a strongly increased risk of developing breast
cancer, they are also vitally important for treatment planning. A treatment plan should
be set up, which is usually done in an interdisciplinary tumor conference in a certified
center, prior to initiating therapy, for which the relevant testing is required. Only
genetic diagnostics will ensure that patients receive the appropriate individualized
therapy, and genetic diagnostics are therefore the first step of any diagnostic workup.
Patients should be fully informed as early as possible. All licensed physicians can
initiate genetic testing for patients with breast cancer. If a pathogenic variant
is identified, the patient must be offered genetic counselling.
Patients with HER2-negative advanced as well as early-stage breast cancer can benefit
from PARPi therapy. In patients with metastatic disease, monotherapy with olaparib
(OlympiAD) or talazoparib (EMBRACA) significantly prolonged progression-free survival
compared with standard chemotherapy [28 ]
[29 ]. In patients with early-stage disease and a high risk of recurrence (OlympiA), (post-neo)adjuvant
olaparib therapy significantly improved not only invasive disease-free survival but
also overall survival compared with placebo [33 ]
[34 ]. Provided the therapy and adverse events are managed well, PARPi are tolerated well
and PARPi-related adverse events do not lead to any meaningful impairment of patients’
quality of life [36 ]
[37 ]
[40 ]. Therefore, genetic testing is not just relevant for prolonging progression-free
survival and improving the quality of life in a metastatic setting but also has a
direct impact on patient survival. For this reason, all breast cancer patients considered
for PARPi treatment, if therapeutically relevant, should be routinely offered genetic
BRCA1/2 germline testing irrespective of HR status, familial history, and age at onset of
disease. Patients qualify for testing if the results will be therapeutically relevant;
from a legal standpoint, these patients should be informed about testing and its potential
relevance.
Recent healthcare research analyses have shown, however, that even after PARPi were
given regulatory approval the testing rates still depend on the patient’s HR status,
age, and familial history; cases with TNBC, young age at onset of disease, and a positive
familial history are tested more frequently [50 ]
[51 ]
.
Guidelines and recommendations (e.g., by AGO e. V.) support BRCA1/2 germline testing as a basis for therapeutic decisions. Without confirmation of a
BRCA1/2 mutation, targeted therapy with PARPi to treat breast cancer is not possible. This
should also be considered for patients with HR-positive breast cancer, patients who
are older at onset of disease, and patients without a positive familial history. Once
an appropriate diagnosis is made, there is no reason not to carry out testing as this
would withhold the option of PARPi therapy from patients for whom it would be suitable,
thereby denying them longer survival times.
