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 »  Abstract
 » Introduction
 »  Pathological Rol...
 »  BRCA Muta...
 »  Role of BRCA<...
 »  Genetic Testing ...
 » Conclusion
 »  References
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REVIEW ARTICLE
Year : 2022  |  Volume : 59  |  Issue : 5  |  Page : 56-67
 

BRCA mutations: Implications of genetic testing in ovarian cancer


1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute, Rohini, New Delhi, India
2 Consultant Medical Oncology, Manipal Hospitals, Bengaluru, Karnataka, India

Date of Submission25-Dec-2020
Date of Decision12-Mar-2021
Date of Acceptance05-May-2021
Date of Web Publication24-Mar-2022

Correspondence Address:
Vineet Talwar
Department of Medical Oncology, Rajiv Gandhi Cancer Institute, Rohini, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_1394_20

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 » Abstract 


Ovarian cancer (OC) is one of the most lethal gynecological cancers with a 5-year survival rate that ranges from 30% to 40%. Breast cancer genes (BRCA1 and BRCA2) play a key role in maintaining genomic stability. Mutations in BRCA1/2 genes lead to the accumulation of double-strand breaks, resulting in tumorigenesis. The risk of developing OC in women with BRCA1 and BRCA2 mutations is 39% and 11%, respectively, by 70 years of age. BRCA1/2 mutation testing is thus important to identify women at greatest risk of developing OC in addition to its impact on diagnosis, prognosis, and targeted therapy. Genetic testing is required to identify the BRCA mutations and thus select patients who can benefit from polyadenosine diphosphate (ADP)–ribose polymerase (PARP) inhibitor therapy. Tumor BRCA mutation testing can detect both germline and somatic mutations allowing implementation of preventive strategies on a broader population. Various international guidelines recommend BRCA1/2 mutation genetic testing in all OC patients irrespective of age and family history. This review focuses on the role of BRCA mutation testing in OC.


Keywords: BRCA1 gene, BRCA2 gene, ovarian cancer, PARP inhibitors, tumor biomarkers
Key Message: BRCA mutations play a significant role in the development, risk identification, prognosis, and treatment of OC.
Tumor BRCA mutation testing can detect both germline and somatic mutations, leading to the identification of a larger population benefiting from PARP inhibitor therapy.
Identification of BRCA mutations allows for germline testing in patients and their relatives for determining at-risk populations.


How to cite this article:
Talwar V, Rauthan A. BRCA mutations: Implications of genetic testing in ovarian cancer. Indian J Cancer 2022;59, Suppl S1:56-67

How to cite this URL:
Talwar V, Rauthan A. BRCA mutations: Implications of genetic testing in ovarian cancer. Indian J Cancer [serial online] 2022 [cited 2022 May 23];59, Suppl S1:56-67. Available from: https://www.indianjcancer.com/text.asp?2022/59/5/56/340520





 » Introduction Top


Ovarian cancer (OC) is the seventh leading cause of cancer-related deaths among women, with 313,959 new cases and 207,252 deaths globally in 2020.[1] India had the second highest incidence of new cases (45,701) and deaths (32,077).[2],[3] Asymptomatic onset of OC causes delayed diagnosis (>70% cases at an advanced stage) and poor prognosis (5-year survival rate: 30%–40%).[4] Mutations in BReast CAncer 1 (BRCA1) and BRCA2 are known to confer an increased lifetime risk of OC.[5] This review focuses on BRCA genes and their function, BRCA mutation testing strategy, and its implication on diagnosis, treatment, and prognosis of OC.


 » Pathological Role of BRCA Genes Top


BRCA1 and BRCA2 genes, located on chromosomes 17q21 and 13q12, respectively, transcribe proteins that are involved in the maintenance of genome stability through repair of DNA double-strand breaks (DSBs).[6] The repair of DSBs in cells is performed by (1) error-free high-fidelity homologous recombination (HR), (2) highly error-prone nonhomologous end joining (NHEJ), and (3) single-strand annealing (SSA).[5],[6] HR is a highly conserved pathway that repairs DSBs by using the intact sister chromatid as a template to repair the break and maintain sequence integrity. BRCA1/2 genes play a key role in this pathway [Figure 1]. BRCA1 surveys the DNA for DSBs, and BRCA2, along with other molecules (e.g., RAD51 complex), attach to the damaged site and repair the DNA. Cell lines with BRCA1/2 mutations have defective HR but intact NHEJ and SSA causing DSBs to accumulate as they are funneled through the error-prone NHEJ and SSA pathways. Cells that completely lack BRCA1 or BRCA2 gene have shown accumulation of DSBs that lead to gross chromosomal rearrangements (GCRs) such as translocations, deletions, broken chromosomes, and triradial and quadriradial structures. It is known that GCRs occurring in the DNA can lead to tumorigenesis.[6] Although germline BRCA1/2 mutations are monoallelic, tumors occur when the second allele also becomes mutated. Thus, tumorigenesis in carriers generally follows a two-hit hypothesis: first “hit” due to an inherited pathogenic mutation of one BRCA allele and second “hit” due to the somatic inactivation of the second wild-type allele.[7] Therefore, genetic testing for germline BRCA mutations in high-risk women and their relatives has a potential life-saving role as it may identify these women early and qualify them for appropriate therapy.
Figure 1: Role of BRCA1 and BRCA2 Genes in DNA Double-Strand Break Repair. DSB = double-strand break; HR = homologous recombination; PARP = polyadenosine diphosphate–ribose polymerase; SSB = single-strand break.
Adapted from: Lord CJ, Tutt AN, Ashworth A. Synthetic Lethality and Cancer Therapy: Lessons Learned from the Development of PARP Inhibitors. Ann Rev Med. 2015;66:455-470. Iglehart JD, Silver DP. Synthetic Lethality – A New Direction in Cancer-Drug Development. N Engl J Med 2009;361(2):189-91.


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The longer disease-free interval after primary chemotherapy and improved overall survival (OS) have been observed in BRCA-mutated patients as compared with nonmutated carriers.[5] Also, in advanced-stage high-grade serous OC (HGSOC), longer progression-free survival (PFS) was independently associated with germline mutations of BRCA.[8] Patients with BRCA mutation have a better response possibly because of the synergism of cell damaging effects. Furthermore, targeted therapy inhibiting other repair mechanisms such as the one mediated by polyadenosine diphosphate (ADP)–ribose polymerase (PARP) in tumor cells harboring BRCA mutations has shown significant improvement in PFS based on the principle of “synthetic lethality” (a phenomenon where simultaneous mutation of two or more genes causes cell death; however, deficiency in either of them is compatible with cell viability).[6] The following sections delve into the implications for BRCA mutations in risk identification, prognosis and treatment of OC, and the importance of tumor testing of these mutations.


 » BRCA Mutation in Ovarian Cancer Top


The lifetime risk of developing OC in women without BRCA mutation by 70 years of age is 1.1%, whereas the similar risk is 39% (95% confidence interval [CI], 22.0%–51.0%) for BRCA1 and 11% (95% CI, 4.1%–18.0%) for BRCA2 mutation carriers.[9] The Epidemiological Study of BRCA1 and BRCA2 mutation carriers that followed 1,509 patients without prior diagnosis of OC found that the average cumulative risk for OC by 70 years of age was 59% (95% CI, 43.0%76.0%) in patients with BRCA1 and 16.5% (95% CI, 7.5%–34.0%) in patients with BRCA2 mutations.[10] In a study of 88 hereditary cases reported that the mean age of diagnosis of OC in patients with germline mutation in BRCA1 was significantly lower compared with BRCA2 mutation (54 years vs. 62 years; P = 0.04).[11]

The incidence of germline mutations in BRCA1/2 genes was found to be varying in different populations. In a large U.K.-based database analysis, of the 2,222 OC patients, 8.1% had pathogenic germline mutations in BRCA genes.[12] Another study in 649 women with invasive OC showed that 11.7% (95% CI, 9.2%–14.8%) patients harbored germline BRCA mutations.[13] A recent analysis of an Indian multicentric prevalence study (n = 239) reported germline pathogenic or likely pathogenic mutation in 61 patients (25.5%; 95% CI, 20.12%–31.54%). Serous type was observed in 159 patients with 48 (30.2%) of them showing pathogenic or likely pathogenic germline BRCA1/2 mutations.[14]


 » Role of BRCA Mutation in OC Risk Identification, Prognosis, and Targeted Therapy Top


Risk identification

The primary objective of genetic testing for pathologic mutations in BRCA1/2 genes is to identify women at the greatest risk of developing breast cancer or OC and to enable appropriate prophylactic strategies. The population frequency of pathogenic BRCA1/2 mutations is very low, ranging from 1:800 to 1:1000 for each of the two genes.[15] However, the mutation prevalence varies considerably between different ethnic groups and geographical areas in the general population. A U.S.-based study estimated the prevalence of BRCA1 or BRCA2 mutation as ∼1:300 to 1:800 among the general population. Another study showed a higher prevalence of BRCA1 or BRCA2 mutation more than 2% in the Ashkenazi Jewish descendants.[16] Mutations are more common in individuals and families that display a cluster of factors such as early onset (<50 years), history of breast cancer, OC, multiple primary cancers (same or related), and breast cancer in men, or in those who are at increased risk for founder mutations (Ashkenazi Jewish, Swedish, Hungarian, Icelandic, Dutch, or French Canadian descent).[16]

Although reproductive, demographic, and lifestyle factors also affect the risk of OC, the most significant risk factor after gender and age is a family history of the disease. Approximately 10% of all OC cases are due to genetic mutations in BRCA1/2 genes, and germline mutations in BRCA1 and BRCA2 genes account for the majority of patients with hereditary OC.[17] A matched case–control study found a relative risk of 4.31 (95% CI, 2.4–7.9), 2.12 (95% CI, 1.2–3.8), and 1.48 (95% CI, 1.0–2.2) in women with an affected first-degree, second-degree, and third-degree relative with OC, respectively.[18]

The risk of ovarian,  Fallopian tube More Details, or peritoneal cancer increases by 39% to 46% (for BRCA1 mutation carriers) and 10% to 27% (for BRCA2 mutation carriers) by age 70 years, in addition to an increased risk for breast, pancreatic, and other cancers.[6],[19] Therefore, pathogenic BRCA mutation testing on a broader population can enable an increased number of relatives to be screened, allowing implementation of a surveillance program and preventive strategies.

Risk reduction strategies

Multiple strategies such as surgery with risk-reducing salpingo-oophorectomy (RRSO) or chemoprevention can be implemented in those who harbor a pathogenic BRCA mutation to reduce the risk of developing OC.[5] A prospective, observational, registry study found that preventive salpingo-oophorectomy was the most effective strategy, associated with an 80% risk reduction in OC, fallopian tube, or peritoneal cancer, and a 77% reduction in all-cause mortality in BRCA1/2 mutation carriers.[20] Chemoprevention using hormonal oral contraceptives has shown to decrease OC risk significantly and can be useful for patients of childbearing age who may not want to opt for RRSO. A case-controlled study with 207 OC patients with BRCA1/2 mutations and 161 matched healthy controls (mutation status unknown) found that oral contraceptives offer a 50% and 60% reduction in risk of OC in BRCA1 carriers (odds ratio [OR], 0.5; 95% CI, 0.3–0.9) and BRCA2-mutated patients (OR, 0.4; 95% CI, 0.2–1.1), respectively.[21]

Prognosis and treatment

BRCA mutation carriers seem to have a survival advantage over the noncarriers. According to a study conducted on 779 Israeli Jewish women with OC, median survival was longer in women with BRCA1/2 mutations (53.7 vs. 37.9 months; P = 0.002), and mortality rate was 28% lower compared with noncarriers over a 6.2 years follow-up period.[22] An observational study using the genomics and clinical data of 316 HGSOC patients (Cancer Genome  Atlas More Details project) found that BRCA2 mutation cases (n = 29) were associated with significantly higher OS (adjusted hazard ratio, 0.33; 95% CI, 0.16–0.69; P = 0.003), and a 5-year survival rate of 61% versus 25% compared with the BRCA2 wild-type patients.[23] A meta-analysis of 33 studies that enrolled 7,745 patients with primary or recurrent OC (more than 80% advanced stage [Stages III and IV]) found that BRCA1/2 mutation carriers had significantly longer OS (hazard ratio, 0.75; 95% CI, 0.64–0.88; P < 0.001) compared with noncarriers. Similar results were obtained when primary OC patients and recurrent OC patients were analyzed separately. The same meta-analysis also reported an improved PFS (hazard ratio, 0.80; 95% CI, 0.64–0.99; P = 0.039) in BRCA1/2-mutated patients compared with noncarriers in response to chemotherapy.[24]

Improvement in response rate to first line and later line of platinum chemotherapy, longer treatment-free intervals, and improved OS have been observed in BRCA mutation–positive women with OC [Table 1].[25],[26],[27]
Table 1: Clinical Trial Results With Platinum Chemotherapy in Ovarian Cancer

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PARP inhibitors and BRCA mutations

Recent evidence suggests that patients with BRCA mutations may also have an advantage of emerging molecular therapies that target other DNA repair pathways. Targeted therapy against PARP enzymes—involved in the repair of single-stranded DNA breaks (SSBs) through the base excision repair pathway—has been successful because of the mechanism of synthetic lethality in BRCA1/2-mutated patients with HR deficiency [Figure 1].[28]

Olaparib was the first PARP inhibitor to undergo clinical development and receive accelerated approval from the U.S. Food and Drug administration in 2014. Among 50 patients (ovarian, primary peritoneal, and fallopian tube cancer) with germline BRCA1 or BRCA2 mutations, 40% of the patients achieved a complete or partial radiologic/CA125 response. A post hoc analysis revealed that the response rate with olaparib was the highest in the platinum-sensitive group (69%), followed by platinum-resistant patients (45%), and platinum-refractory patients (23%).[29] Several randomized, Phase 2/3 trials evaluating PARP inhibitors (olaparib, rucaparib, niraparib, veliparib, and talazoparib) have reported improvement in PFS and OS in various settings in BRCA-mutated or other HR-deficient OCs. Preliminary results of some of these studies are summarized in [Table 2].[30],[31],[32],[33],[34],[35],[36],[37],[38],[39]
Table 2: Clinical Trial Results With PARP Inhibitors in Ovarian Cancer

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A study that identified germline and somatic BRCA mutations in DNA from OC tissue and compared the efficacy of PARP inhibitors found that BRCA1 and BRCA2 mutations in OC were associated with a significantly improved PFS as compared with BRCA1/2 wild-type (BRCAwt) cancer (hazard ratio, 0.65; 95% CI, 0.44–0.98; P = 0.032). The median PFS in patients with BRCA1/2 germline-mutated OC was not significantly different from that in patients with somatic BRCA mutations.[40] Hodgson et al.[41] used tumor samples from the pivotal trial where olaparib maintenance monotherapy was given to HGSOC patients and found BRCAwt tumors with additional loss of function. HR mutations showed a significant response to olaparib when compared with placebo. Thus, PARP inhibitor treatment not only is effective in OC patients with germline BRCA mutations but also shows a significant response in OC patients with somatic BRCA mutations and other HR loss of heterozygosity (LOH) deficiencies. Consequently, tumor testing in OC patients for BRCA mutations and BRCA-like defects seems to be more advantageous than pure germline testing; considering this will significantly expand the population base that may benefit from PARP inhibitor therapy.

PARP inhibitors are now approved as first-line maintenance for BRCA1/2-mutated patients, as maintenance in platinum-sensitive relapsed setting irrespective of BRCA status and as treatment in third line and beyond setting in relapsed BRCA1/2-mutated patients.[38]


 » Genetic Testing for BRCA Mutations and other HR Deficiencies Top


Germline BRCA mutation testing

It is imperative to provide genetic assessment for BRCA mutations to identify and select only those patients who are likely to carry the pathogenic BRCA1/2 mutations because of the implications on diagnosis, prognosis, and now molecular therapy of OC. It was presumed that a universal testing strategy might identify all such patients, but an exhaustive germline genetic testing of all probands with OC could be a challenge, and focus on the high-risk population would optimize the use of resources. The widely accepted clinical criteria for germline genetic testing and counseling is family history and age of cancer onset. Based on these criteria, pathogenic germline mutations in BRCA1/2 are typically identified in 12% to 15% of tested cases; however, clinical criteria alone may miss some carriers.[6] Risk prediction models such as the BRCAPRO, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), or the Manchester Scoring System have been developed to assess the probability of a pathogenic BRCA1/2 mutation in a given individual depending on their family history with varying degrees of validation.[15] The BRCAPRO is a statistical model, with associated software, for calculating the probability that an individual carries a germline deleterious mutation of the BRCA1 and BRCA2 genes, based on age, personal and family history of breast cancer, and/or OC, ethnicity, and age at diagnosis using Mendelian inheritance and Bayesian analysis approach.[42] Likewise, BOADICEA is a computer program that calculates the risks of breast cancer and OC in women based on their family history.[43] Unlike the two computer-based programs, the Manchester Scoring System allocates a score to each affected individual in a family and computes the sum of the scores in the maternal and paternal lineage to determine the need for genetic testing.[6] Each of these models has some limitations with regard to their predictive ability, for example, the BRCAPRO model significantly underestimates BRCA1/2 mutations at BRCAPRO scores less than 40% in the whole OC and HGSOC populations.[42]

Although the prevalence of BRCA pathogenic mutations positively correlates with the family history in the majority of cases, BRCA mutations have been also noted in the absence of a strong family history.[44] Furthermore, lack of accurate family history and the requirement for knowing the mutation status when initiating PARP inhibitor therapy means that testing only high-risk groups is inadequate, and instead referring all OC patients for genetic testing seems more appropriate. The National Comprehensive Cancer Network (NCCN), Society of Gynecological Cancer, and individual country guidelines now recommend that all women with OC regardless of family history or age of onset should receive comprehensive BRCA1/2 genetic counseling and be offered BRCA1/2 mutation testing [Table 3].[45],[46]
Table 3: Guidelines for Germline Genetic Testing of BRCA mutations

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However, germline genetic testing is not being followed as extensively as recommended. Norquist et al.[47] found that one third (37/107) of the BRCA1/2 mutations present in their OC study population had not been identified through clinical genetic testing, specifically those who were diagnosed at older ages and lacked a strong family history. Similarly, Demsky et al.[48] found that only 23% of women with invasive OC underwent genetic counseling, and this likelihood further decreased for women diagnosed at older ages. Thus, a referral bias remains wherein women who lack a strong family history or who are younger at diagnosis are less likely to receive BRCA1/2 genetic testing. Besides, the associated cost, the need for genetic counseling for patients to correctly understand the test results, and a longer turnaround time appear to limit the use of germline genetic testing in a clinical setting. Additionally, somatic BRCA mutations and changed mutation profile of the tumors with disease progression and/or chemotherapy may be missed by germline testing alone.[44] A tumor testing for BRCA mutations and other such mutations may overcome these disadvantages of germline BRCA mutation testing and facilitate a comprehensive approach to genetic testing.

Tumor BRCA mutation testing

BRCA1/2 somatic mutations have been identified in patients with OC who lack a strong family history. Somatic pathogenic BRCA mutations are reported to be present in ∼7% of OCs in first-line or platinum-sensitive relapsing patients. Furthermore, PARP inhibitors are active irrespective of whether a BRCA1/2 mutation is germline or somatic in origin as LOH of both copies of BRCA1 or BRCA2 in the tumor is observed in both germline or somatic mutations.[44],[48] This prevalence represents a significant population of women who could benefit from PARP inhibitors and about one third of all BRCA-mutated patients.[48] The evidence with PARP inhibitor efficacy in OC populations with somatic BRCA mutations and other HR deficiencies indicates that tumor testing will now be necessary to make treatment decisions for patients with OC to determine their suitability for PARP inhibitor therapy.

Tumor BRCA1/2 mutation testing has emerged as a powerful tool to discover and identify mutations in OC patients.[49] Formalin-fixed paraffin-embedded (FFPE) specimens provide better quality DNA for BRCA1/2 mutation testing. Recommended fixation time varies from 8 to 48 hours, which is dependent on the specimen or tissue block size.[49] However, sometimes FFPE blocks cause technical challenges in testing because of fragmentation and chemical modification of DNA, leading to polymerase chain reaction amplification failures and false-positive sequencing results.[44] Additionally, the overall low yields of amplifiable DNA from tumors can be a limiting factor given that the BRCA1/2 genes have large coding regions. FFPE analysis may also be misinterpreted because of the process-introduced artifacts in the sample DNA.[49] Therefore, the validated methods analyzing germline BRCA1/2 mutations may not be suitable for the low-quality, highly fragmented, low-yield DNA from tumor samples. Amplicon-based or hybridization capture–based next-generation sequencing (NGS) approaches for analysis of FFPE material are currently the best available and highly recommended options for tumor testing to identify BRCA1/2 mutations. NGS has the ability to analyze a limited quantity of DNA from clinical samples and identify pathogenic BRCA1/2 variants irrespective of their large size. The Sanger sequencing approach requires a large amount of DNA for screening and is less sensitive.[49] NGS-based testing can best detect point mutations and small insertions and deletions (indels). Large indels that are frequently reported with BRCA genes are best identified using multiplex ligation-dependent probe amplification combined with single-molecule molecular inversion probe–based targeted NGS approach.[50] Despite the available evidence, NGS methods need to be further standardized for variant calling and bioinformatics pipeline layout for the validation of results.

Tumor testing for BRCA and BRCA-like mutations in the HR pathway has several advantages. HR deficiency related to BRCA1/2 genes is observed in 19% to 22% of OC tumors, 10% to 15% with pathogenic germline mutation, 2.5% to 8.5% with somatic mutation, and 10% to 15% with promotor hypermethylation of BRCA1. Germline mutations, somatic mutations, and promoter hypermethylation of BRCA1 appear mutually exclusive in OCs.[50] Given the genetic heterogeneity of the mutation spectrum, tumor genetic testing for BRCA mutations will aid to maximize the number of patients who can benefit from PARP inhibitor treatment.[49]

Since germline genetic testing is protected or restricted by law and pretest genetic counseling is mandatory in many countries, it significantly adds to the cost and the turnaround time to get the results. However, tumor testing for somatic mutations for targeted molecular therapy is now a well-accepted approach practiced in the management of several malignancies.[49] The FLABRA study carried out in 376 patients with OC identified both germline and somatic mutations in a single test.[51] The prevalence of BRCA mutations detected in the tumor was 30%. A single tumor testing for BRCA mutations, identifying both the germline and somatic mutations can potentially save cost and time. Additionally, tumor testing requires less extensive genetic counseling at the inception, and there will be less involvement for the wider family unlike for germline testing. Once pathogenic mutations in the tumor are suspected coupled with other familial histories and known risk factors, a focused germline testing effort can be applied, facilitating an overall reduction in genetic testing.[48]

Although both these sequences of testing have been discussed extensively, in the current era, testing both germline and somatic mutations has importance in OC. The current thought process is that if germline testing is positive, then somatic testing is not required; if germline testing is negative, then somatic testing should be performed. If somatic testing is performed primarily, negative results should be reconfirmed with germline testing. Positive somatic testing results will need germline testing to decide on the hereditary nature of the mutation. In an ideal scenario, BRCA mutation testing should be done at the time of OC diagnosis; however, if missed, patients can also be referred for testing at any point in the pathway [Figure 2].[52] A streamlined testing approach will lead to shortened turnaround times by providing combined genetic testing and counseling, with high acceptance and satisfaction among patients and treating oncologists.[53]
Figure 2: The BRCA Mutation Testing in Ovarian Cancer: Patient Journey. *Patients with variants of uncertain significance should be referred for genetic counseling but will not be eligible for PARP inhibitors therapy. †If family history of a hereditary cancer syndrome, offer referral to genetic counseling. PARPi = Polyadenosine diphosphate–ribose polymerase inhibitors; VUS = variants of uncertain significance
Adapted from: Vergote I, Banerjee S, Gerdes AM, van Asperen C, Marth C, Vaz F, et al. Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients. Eur J Cancer 2016;69:127-34.


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Importance of BRCA mutation testing

The introduction of BRCA mutation testing has a positive therapeutic impact as many patients benefit from anti-PARP-1 targeted therapies or other similar novel drugs being investigated. Additionally, BRCA1/2 mutation testing can identify advanced mutations that might involve family members, facilitate the diagnostic process and family management, and prevent the occurrence of secondary cancer.[44] Also, BRCA1/2 mutation reversal can identify patients resistant to treatment.[49]

Integrating BRCA1 and BRCA2 mutation testing in the patient's pathways

The distinct advantages of BRCA mutation tumor testing necessitate that tumor testing should be strongly advised in routine clinical practice to facilitate early diagnosis, ensure access to modern therapies, identify mutations that might have grave implications to family members, and even prevent secondary cancers.[44] Ideally, tumor testing should be initiated factoring in the local turnaround times for testing, waiting time, and the potential need for genetic counseling, to be clinically relevant for the patient.[49] Although no specific time for such testing has been defined, most patients are amenable to early testing and thus this approach is advantageous. BRCA mutation testing was previously carried out based on family history or age, but now all women diagnosed with ovarian, fallopian tube, or peritoneal carcinoma regardless of age or family history should receive genetic counseling and be offered BRCA1/2 genetic testing, as recommended by different guidelines (the NCCN, the American College of Obstetricians and Gynecologists, and the Society of Gynecologic Oncology) guidelines [Table 3].[45]


 » Conclusion Top


The role of BRCA mutations in the development, risk identification, prognosis, and treatment of OC is increasingly accepted. The recent American Society of Clinical Oncology (ASCO) guidelines also recommend germline testing for BRCA mutations in all women with OC.[54] Identification of a BRCA mutation may not only help the afflicted patients but also allow for genetic testing to be performed on relatives, thus increasing the potential to prevent OC in a wider population. In patients who do not carry germline mutations, tumor tissue–based somatic testing should be performed. PARP inhibition, which significantly improves outcomes in women who harbor BRCA mutations, necessitates additional tumor testing for BRCA mutations. BRCA mutation tumor testing, in addition to germline testing, for BRCA mutations is advantageous as it expands the patient population that could benefit from PARP inhibitor therapy, reduces the need for genetic counseling at the outset, and detects both germline and somatic mutations in many situations. Globally, tumor BRCA mutation testing in all OC patients requires strong harmonization and implementation irrespective of family history to optimize diagnosis and get optimal access to targeted therapies. Thus, the continued advances in our understanding of BRCA mutations and their role in OC may substantially improve the long-term outcomes for patients with this lethal disease.

Acknowledgments

The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Ms. Prajakta Nachane M. Pharm. from Covance Scientific Services and Solutions Pvt. Ltd. in accordance with the GPP3 guidelines (http://www. ismpp.org/gpp3).

Financial support and sponsorship

AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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