INTRODUCTION
In Brazil, ovarian cancer has a prevalence of 6,650 new cases every year, corresponding to the seventh cause of cancer mortality in women.[
[1]
] In the past few years, the primary treatment for advanced ovarian cancer (OC) consisted mainly of cytoreductive surgery and chemotherapy. Few new therapeutic approaches provide promising benefits for recently diagnosed patients, and unfortunately significant part of them endure relapses of this disease.[
[2]
] Increasingly advances in personalized medicine and new therapeutic proposals depend upon assessing genetic mutation status to provide an appropriate and assertive treatment decision. The necessity of understanding prognostic and predictive factors and assessing hereditarian information is well known, especially in light of new and promising target therapies for epithelial ovarian cancer (EOC).[
[3]
]
Oncology guidelines have been often revised to contemplate precision medicine advances and include genetic testing criteria (including BRCA gene testing) for ovarian cancer and genetic counseling recommendation in a movement to evaluate genetic risk assessment.[
[4]
[5]
] However, there are few accurate data about BRCA mutation testing recommendation in clinical practice for advanced OC patients. Recent clinical trials showed the importance of earlier treatment on OC BRCA mutated patients, bringing awareness about the right time of testing recommendation for better decisions concerning patients' treatment choices.[
[3]
[5]
]
Thus, assessing information about the genetic background in OC patients allows the medical community better to understand cancer risk and predictive and prognostic factors, leading to better decisions. In this context, understanding the mutation prevalence is critical. However, most of the available data about population genetic mutation come from clinical trials and epidemiologic researches, and few data are available showing real-world results from the clinical scenario. Nonetheless, few data are available showing the introduction of genetic testing as a biomarker during patient diagnostics in the context of clinical practice. In a scenario where everything is new, there is always missing some puzzle pieces.[
[2]
[7]
[8]
[10]
[11]
]
Thus, this work aimed to discuss genetic testing recommendations in Brazil's clinical practice, bringing information about the actual scenario of Brazilian clinical practice. Focusing on BRCA 1/2 mutation testing for advanced OC patients, evidencing when the test is requested during the patient journey, discussing the implications of mutated patients, and the primary health care professionals that should be involved such as oncologists and where there is strong the patient history predictive of an inherited genetic mutation an oncogeneticist should be participating on this patient journey. We expect to bring to light the main concerns and barriers about genetic testing that may be guiding future medical and diagnostics education, providing a significant background to a transformation in oncology clinical practice hopping for better patient care.[
[12]
[13]
[14]
]
MATERIAL AND METHODS
The survey: AstraZeneca and Ipsos Brazil (a market research contractor) defined a survey to inquiry experienced Brazilian oncologists about their BRCA testing recommendation during OC patients' journey (Appendix I). Ipsos conducted this research upon request of AstraZeneca Brazil.
The questionnaire focused mainly on how frequently the oncologists recommended BRCA mutation testing when testing was requested and the main difficulties for the testing recommendation. The survey was built based on the expertise from AstraZeneca and Ipsos on oncology. Ipsos collected the answers after the physicians signed the informed consent to participate on the survey. Oncologists were randomly chosen from different regions of Brazil. The number of answers from each region was balanced. The criteria for respondent's selection included: time as oncology specialists and possible experience treating ovarian cancer, must spend at least 50% of the time in direct patient care, and must be chemotherapy prescriber.
The specialists chosen by Ipsos received an online questionnaire (duration of 30 minutes) in four different waves (wave 1: May 2018 | wave 2: September 2018 | wave 3: November October 2018 | wave 4: June 2019). Approximately 100 survey answers were expected in each wave, few physicians were kept in all waves, meaning that most of respondents were different across all waves. When this number was reached, Ipsos stopped contacting new respondents the total number of contacted physicians were not recorded. The sampling margin of error was 4.9 percentage points.
Demographic information and specific questions about the clinical practice related to BRCA testing for OC patients formed the questionnaire. The compiled answers were organized and described in the results section of this article and were the primary source of information for this article.
Statistical methodology: the results of time as oncologists ([Table 1]) is expressed in the average number of years, after medical residency, applied at the oncology specialty. The number of patients with ovarian cancer treated in the previous three months and the number of patients that received a BRCA testing recommendation in the private sector are expressed by the average number of reporter respondents ± standard deviation.
Table 1
Respondents-demographic characteristics.
|
Wave 1
|
Wave 2
|
Wave 3
|
Wave 4
|
|
Number of oncologists respondents
|
110
|
120
|
110
|
100
|
|
Gender-(male/female)
|
57/43%
|
54/46%
|
54/46%
|
57/43%
|
|
Time as oncologist (years)
|
9
|
10
|
9
|
9
|
|
Dedication of time (%)
Public hospital
Private clinic
Private hospital
CACON[**]
University
|
42
36
14
8
0
|
31
42
18
8
1
|
38
34
14
13
1
|
36
33
14
15
1
|
|
Country region
(Region, %[*] )
|
|
Southeast=56 South=26
Northeast=14
North and Center West=4
|
|
The number of participants, percentage, the average number of years, percentage, respectively, represent the results.
* Region of respondents from wave 4, missing data for w1, w2, w3.
** CACON: High complexity health unity.
All other results are expressed by the percentage calculated based on the respondent's choice of answers.
Literature search: a literature search in the leading medical database, such as PubMed, Google Scholar, EMBASE, was conducted, using the combined terms, “ovarian cancer,” “ BRCA testing recommendation”; “guidelines,” “treatment” “genetic counseling”. The main articles and abstracts were selected and retrieved, and used as scientific background only for the discussion section.
RESULTS
The results represent the compiled responses obtained in each wave (w), as described in the methods section. The compiled results are presented in[Figure 1]
. The number of answers in each wave was w1=110, w2=120, w3=110, and w4=100. The oncologist's respondents were distributed in four regions of the country.[Table 1]
shows the demographic and gender data. The survey was answered exclusively by Brazilian oncologists, and the respondents perform their clinical practice in both the public and private health sectors. The compiled results showed that most of their time is dedicated to patients in the private care sector, including private clinics and hospitals ([Table 1]). Also, time dedicated in the public sector is lower, observed across all waves ([Table 1]).
Figure 1 Main results obtained by survey responded Brazilian oncologists with the average number of patients with ovarian cancer, the average number of patients referred to BRCA mutation testing reported during the surveys, and the main obstacles pointed during the research.
Regarding OC patients, the oncologists interviewed reported that in the previous three months (starting from the moment they received the questionnaire), they were treating on average in w1=3, w2=4, w3=3, and w4=5 patients with OC. When inquired about BRCA testing recommendations related to their practice in the private sector, they indicated that this test was not recommended for all patients. In waves 2, 3, and 4, only an average of three patients in each wave respectively, received a testing recommendation from private institutions (wave 1 data not collected) ([Table 2]).
Table 2
Patients and BRCA testing recommendation.
|
|
Wave 1
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Wave 2
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Wave 3
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Wave 4
|
|
Average Number of patients with ovarian cancer treated in the previous three months (n)
|
3±4
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4±3
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3±4
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5±5
|
|
Range (n)
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1-19
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1-11
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1-19
|
1-16
|
|
Patients Distribution in Public/ private sector (%)
|
24%/76%
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27%/73%
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28%/72%
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29%/71%
|
|
Average number of patients that received a BRCA testing recommendation in the private sector (n)
|
[*]
|
3±3
|
3±3
|
3±3
|
|
Range (n)
|
[*]
|
1-11
|
1-10
|
1-10
|
Results represent the average number of patients reported by respondents ± standard deviation. Percentage and the average number of patients reported by respondents, respectively.
* Missing data for w1.
When inquired about the timing of testing recommendation, most specialists indicated that their central conduct would make the recommendation during the initial patient's diagnostic process w1=44%, w2=50%, w3=58% and there was an increase in the number of oncologists that requested the test early on initial diagnostics on w4=64%. Some respondents stated that testing recommendations would happen during the first line of treatment or chemotherapy. A reduction on wave 4 (4%) is noticeable in the BRCA testing recommendation later on, in a moment before the second line of OC treatment when compared to w1=9%, w2=5%, and w3=5% ([Table 3]).
Table 3
Timing of
BRCA
testing recommendation for ovarian cancer patients (single choice) (%).
|
Wave 1
|
Wave 2
|
Wave 3
|
Wave 4
|
|
During initial diagnostic (%)
|
44
|
50
|
58
|
64
|
|
After the first line of chemotherapy treatment (%)
|
22
|
30
|
19
|
19
|
|
After the beginning of treatment (%)
|
25
|
15
|
17
|
12
|
|
Before the second line of treatment (%)
|
9
|
5
|
5
|
4
|
|
Total
|
100%
|
100%
|
100%
|
100%
|
Percentage indicated by the sum of answers represents the results.
Considering this, we went further and questioned the type of sample evaluated. The results showed that in wave 1, the first option pointed by the oncologists would be tumor testing (51%) followed by blood/ saliva (35%), and only 14% would evaluate the tumor sample and check on blood/saliva to confirm mutation origin (somatic versus germline). In wave 2 (43%) of the participants pointed that they would refer patients to blood/saliva evaluation, and 43% would evaluate the tumor, and, likewise, in wave 1, 14% of answers pointed that they would recommend both blood/saliva and tumor testing.
In waves 3 and 4, most of the respondents pointed that the first option would be recommending blood/ saliva testing (46% and 47%, respectively), and the second most frequent option would be tumor testing (37% and 38%, respectively). And, as observed in the previous waves, the less recommended option would be testing both blood/saliva and tumor samples (17% and 15%, respectively) ([Table 4]).
Table 4
Patients' proportion referred to different testing sample types (%).
|
Wave 1
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Wave 2
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Wave 3
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Wave 4
|
|
Blood/saliva (%)
|
35
|
43
|
46
|
47
|
|
Tumor (tissue) (%)
|
51
|
43
|
37
|
38
|
|
Blood/saliva and tumor (tissue) (%)
|
14
|
14
|
17
|
15
|
|
Total
|
100%
|
100%
|
100%
|
100%
|
Percentage indicated by the sum of answers represents the results.
Considering the number of patients that received a test indication ([Table 2]), we inquired about the main reasons restrict BRCA testing for all OC patients. In a multiple-choice panel, they pointed the main barriers for testing ([Table 5]). The most frequent reasons for refrain BRCA testing recommendation in w1=36%, w2=26%, w3=18%, and w4=38% were cost associated with the exam and lack of patient's reimbursement. It is important to mention that this answer did not specify the sample type (blood/saliva or tumor tissue) ([Table 5]).
Table 5
Main reason to restrict BRCA testing for all ovarian cancer patients (multiple choice) (%).
|
Wave 1
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Wave 2
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Wave 3
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Wave 4
|
|
The costs are restrictive
|
36
|
26
|
18
|
38
|
|
Limited genetic counselors
|
13
|
16
|
16
|
19
|
|
The test is not reimbursed
|
27
|
23
|
16
|
17
|
|
Low mutation risk
|
11
|
14
|
15
|
11
|
|
Timing for results versus the necessity of fast treatment decision
|
9
|
6
|
13
|
11
|
|
Patient does not want to know the results due to family implications
|
8
|
15
|
14
|
10
|
Sum of answers represents the results and respondents were allowed to choose more than one option.
Another barrier associated with testing recommendation restriction was limited access to genetic counselors, 13%, 16%, 16%, and 19% in waves 1 to 4, respectively. This answer implies the oncologist recognizes the necessity of genetic counselors' involvement in OC patients' care. The time to obtain results versus the necessity for a prompt treatment decision was also mentioned as a reason not to recommend testing (w1=9%, w2=6%, w3=13 %, and w4=11%).
Some traits associated with the disease, such as low mutation risk, were also indicated as a reason for not recommending BRCA testing (w1=11%, w2=14%, w3= 15%, and w4=11%). Patients' refusal due to family implications was also pointed as a reason for not testing patients (w1= 8%, w2=15%, w3=14%, and w4=10%) ([Table 5]).
DISCUSSION
In the past few decades, the main treatment for advanced epithelial ovarian cancer has been cytoreductive surgery and platinum-based chemotherapy, leaving patients with few options on this daunting disease and, consequently, very high recurrence rates.[
[15]
[16]
[17]
]
The scientific and medical community is always in search of advances in cancer treatment. A recent proposal relying on genetic sequencing and target therapies allowed oncologists to be assertive about therapeutic choices. We cannot forget the importance of genetic testing. The inclusion of clinical practice is associated with preventive actions. In this scenario, the involvement of a scarce specialty, the oncogeneticist, is mandatory to compose a full therapeutic approach.[
[14]
] Since the description of BRCA gene mutation and the association with breast and ovarian cancers, the medical community has asked how to follow-up patients who have the mutation. In other words, the medical community miss specialists and guidance in oncogenetics.[
[18]
[19]
]
For a better-paved discussion on this matter, let us take a step back and refresh molecular biology concepts. Cell genetic content is susceptible to external and internal injury, leading to single and/ or double-strand breaks. Double-strand breaks are rarer, nevertheless more dangerous, can lead to loss of genetic information, and are associated with chromosomal instability on mitotic cells. BRCA genes (encode proteins) act on genes double-strand break repair, presenting antitumor growth properties.[
[20]
]
Homologous recombination repair (HRR) is a complex repair mechanism that prevents DNA double-strand breaks and counts on BRCA gene action.[
[21]
[22]
] Deficiency in (HRR) is one hallmark of cancer, and it is linked to some tumor types, including epithelial ovarian cancer.[
[23]
[24]
]
The poly (ADP-ribose) polymerase (PARP) enzymes also participate in mechanisms that maintain DNA integrity. New therapeutic approaches, with PARP inhibitors, provide an option for OC treatment. The mechanisms of action rely on inhibiting DNA repair, specifically single-strand breaks. Those defects will be accumulated and, in an environment where another genetic deficiency in homologous recombination repair is already present, such as observed in BRCA gene mutation, there is a lack of double-strand breaks repair. This sum of defects will lead to cell death and antitumor activity due to the accumulation of DNA defects (one basal and a second introduce). This mechanism is described as synthetic lethality.[
[24]
[25]
]
Enough of molecular biology. Let us explore new horizons. Recently, with the proposal of targeted therapies, such as PARP inhibitors, a new horizon for EOC treatment arose.[
[24]
[26]
] However, in some of those new targeted therapies, genetic testing can be required as a biomarker to identify those patients who would benefit from this treatment, introducing the necessity of genetic diagnostics, such as BRCA 1/2 mutation testing, on the patient journey.[
[3]
]
Traditionally the assessment of BRCA mutation has been required in the clinical practice to identify patients' family members who are at higher risk of cancer development and can benefit from genetic counseling. Nonetheless, the medical community identified a difficulty associated with the limited number of genetic counselors, and some new methods are being proposed to fill out this gap.[
[13]
[14]
]
The sample type used to assess patients' BRCA status raises some implications and bring knowledge about the mutation origin. Testing the tumor will bring information only about the tumor environment, and this result will possibly guide the oncologist's treatment decision. On the other hand, testing the patient's blood/saliva (germline) will open a different knowledge level and bring implications to patients' families due to the hereditary associated with this genetic background.[
[5]
]
Do we need to test? Are there many patients that justify that?
A recent study evaluated the prevalence of BRCA mutation in the recently diagnosed OC Brazilian population. The results demonstrated that one in four patients (26,7%) had a BRCA1 or BRCA2 gene mutation. They considered mutation found in the tumor and subsequently verified that 63% had a germline origin). Moreover, 14,8% had a somatic mutation. This data reinforces the importance of testing recommendations due to the frequency of BRCA 1 and 2 gene mutation in the Brazilian population.[
[10]
[11]
]
Recent clinical trials have shown that patients with BRCA gene mutation may benefit from PARP inhibitor therapy, but some other trials bring data about other genes and diagnostics methodologies to identify patients.[
[6]
[24]
] Thus, the advances in medicine and diagnostics with gene sequencing allowed the adoption of BRCA1 and BRCA2 genes as a biomarker, beyond of assess family risks and bring relevant information for patients with breast cancer or OC. Testing allowing oncologists to predict patients that would benefit from PARP inhibitors therapy.[
[13]
[27]
]
Hence, in this work, we decided to inquiry oncologists, mapping the genetic testing recommendation in Brazil during a year, in four different periods referred to as waves.[
[12]
] This work's main objective was to report the BRCA gene testing recommendation in the context of Brazilian reality by oncologists, understand the sample of choice, and discuss the main concerns for BRCA gene testing, which may be guiding for future medical and diagnostic education.
What is being done from a clinical practice perspective?
The oncologist's respondents were well distributed in Brazil regions per previous studies showing medical and demographic distribution. Some criteria such as time as oncologist specialist, gender, experience in OC treatment, and dedication time in the public versus private health sector were considered. The number of answers distributed in each country's region reflects its medical demography.[
[28]
[29]
]
The data pooled from the four waves during a year showed that the oncologists' respondents reported that they treated in average 3 to 5 (range 1-19) patients with OC in the previous three months from the survey response and eventually only 3 (range 1-10) patients received their recommendation to testing BRCA mutation. In the meantime, concerning wave 3 and wave 4, there was a release and approval for a PARP inhibitor as maintenance therapy for patients recently diagnosed in the country; we did not notice an increase in testing recommendation due to this approval.
A survey conducted in Hong Kong showed that BRCA testing rates could be as low as 28% of the recommendation for OC patients, highlighting that the medical community should have a better agreement and consensus on BRCA genetic testing for those patients. Another recent work that analyzed retrospective data showed an increasing trend to refer patients with ovarian cancer to be tested, but it is consensus that the reality is far from ideal.[
[12]
[30]
]
Another critical subject is about the timing for testing. Genetic testing results can take few weeks to months to be released, being time-consuming. Considering the importance of this data to oncologist's treatment decisions, we proceeded to inquire when the test recommendation was made, with a single choice answer about BRCA gene testing timing during OC patients' journey.
Surprisingly, most of the respondents acknowledged that they recommended BRCA gene testing during the initial diagnostic period, and an increase in wave 4 to 64% of respondents that made the testing recommendation in this period was noted when compared to the previous waves (w1=44%, w2=50%, and w3=58%). We believe that the positive result of clinical trials with maintenance PARP inhibition may have influenced their decision and changed their clinical practice, bringing a testing recommendation to an early period. Although we evidence this movement, it is clear that testing recommendations must be more homogeneous between specialists that treat OC.[
[3]
[17]
] However, many respondents have reported testing later during OC patients' journey, w1=25%, w2=15%, w3=17%, and w4=12%. This result would indicate testing after the beginning of OC treatment. In particular, these results let us question what might influence the oncologist's decision to delay patients testing. A recent study pointed to the lack of local evidence as a factor for broadening genetic testing, highlighting the absence of association of family history of pancreatic cancer, prostate cancer, and breast cancer in the local population as a predictor risk for OC. Thus, local epidemiologic data may convince local oncologists and influence guidelines for OC BRCA testing.[
[12]
]
Most respondents would recommend testing blood/ saliva or tumor separately. In all waves, the sample of choice would be blood/saliva evaluating BRCA germline mutation. This kind of sample brings information about hereditary mutation and has an impact on information about family background. In this case, according to international guidelines, the involvement of a specialist in oncology and genetics would be required to make proper genetic counseling.[
[31]
]
Oncologists need to partner with specialists in oncogenetics. Inherited genetic alterations are associated with cancer are estimated in about 5% to 10% of all tumors. Considering this scenario, it a consensus that a genetic counselor's involvement in these cases has a crucial role in family at-risk evaluation, subsequently providing counseling on preventive actions. Thus, assessing germline mutations is mandatory to provide proper patients and families' assistance.[
[8]
]
The second most frequent option was testing the tumor (tissue) sample. When starting with a tumor (tissue) testing, both somatic and germline BRCA mutation can be detected. A growing body of evidence shows that starting testing by the tumor would be more cost-effective due to a possible improvement in efficiency by referring only patients with a tumor BRCA mutation to further blood/saliva testing to verify a possible germline mutation rather than all patients with OC.[
[12]
] It is essential to mention that this approach is a challenge due to the lack of coverage by the private health care providers for tumor testing in the Brazilian reality.[
[12]
[32]
]
Contrary to tumor testing, a recent guideline from ASCO (American Society of Clinical Oncology) stated that germline testing should be performed first, and only in negative mutation results, the tumor test should proceed, showing once more lack of consensus.[
[5]
]
The respondents were also asked why the oncologists would not recommend BRCA genetic testing in a multiple-choice questionnaire. In all waves, the answers related to patient's reimbursement and testing cost were the main concerns. In Brazil, two main initiatives govern health care: private and public. In the public sector, the Unified Health System or SUS ( Sistema Único de Saúde ) presents a very restrictive reality regarding new technologies and diagnostics assessment.[
[28]
]
In contrast, the private sector provides broader health access to the insured patients, and periodically the National Supplementary Health Agency (ANS) revises health procedures that should be covered by private health plans.[
[33]
]
For germline BRCA genetic testing, ANS has a statement declaring that all patients with EOC should have the BRCA testing covered in Brazil. Thus, in the private sector, the test should be covered by private health care plans, and the patients should receive genetic counseling as well. It is critical to mention that only approximately 25% of the Brazilian population has private health insurance coverage. Moreover, emerging data brought the discussion that testing ovarian cancer patients to detect BRCA mutation is cost-effective, and in a long-term perspective, it may reduce deaths and cancer treatment burden.[
[34]
[35]
]
Despite this advance from ANS regulation for the private health care sector, further steps are acknowledged as required for all patients to get the testing covered.[
[31]
]
The lack of genetic counselors was also mentioned as a reason for not recommending genetic testing. Some brazilian services are reference on genetic counseling, and a great effort is made to give proper genetic counseling. However, considering the country dimension, the number of professionals specializing in genetic counseling for oncologic patients is still deficient.[
[8]
]
In Brazil, genetic counselors are scarce, presenting as a bottleneck. The main reasons for this incipiency are the few medical specialization programs available in the country and the concentration of professionals in southeast and south regions of the country.[
[14]
]
There are numerous other obstacles to overcome. Some of them are associated with genetic testing, including the bureaucracy associated with reimbursement, from the moment of requesting until getting the result report released. The entire process is time-consuming, and there is no clear description of patients on how to get tested. In high-income countries, the timing for schedule an appointment with a genetic counselor can be 12 to 15 weeks, showing that assess to this professional is a challenge in time and number of professionals to be overcome in our country and worldwide.[
[8]
[14]
[29]
[31]
] As BRCA testing has a significant predictive value for OC patients' treatment decisions, straightforward strategies should be studied parallel with genetic counselors' training in low and middle-income countries, in line with high-income countries' experience.[
[14]
] Low mutational risk and some patients' trait cancel testing necessity were less frequent options pointed as reasons not to recommend testing. The prevalence of BRCA mutation in the OC population is 14%, and more recent data revealed that in the Brazilian population with the prevalence in high serous ovarian cancer patients is 26%. Thus, the frequency of mutation is high and could be predictive of disease outcome and guide treatment decision, reinforcing that BRCA gene testing should be recommended to guide OC better treatment decision.[
[14]
]
These answers let us think that medical education and more effective guidelines would be required for professionals that treat OC once the recent data proved that the BRCA mutation frequency is high on our population and there is a better care option for treatment available.[
[10]
[11]
[36]
[37]
]
