Ovarian cancer and BRCA mutation genetic testing: the Brazilian reality

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 ^]

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.

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.

The results represent the compiled responses obtained in each wave (w), as described in the methods section. The compiled results are presented inFigure 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).

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).

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).

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).

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).

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).

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 ^]

Our work showed that in the Brazilian reality, BRCA gene testing had not been recommended for all patients with advanced ovarian cancer in Brazil, and it has not improved within the study time frame. Despite new promising OC therapies and medical community efforts, our reality is far beyond ideal in genetic testing. There is a striking discrepancy in healthcare sectors and a lack of consensus in terms of genetic testing. Actions such as medical education, testing affordability, and new proposals for genetic counseling may gradually improve oncologists' clinical practice aiming for better care to ovarian cancer patients.