BRCA testing and management of BRCA-mutated early-stage breast cancer: a comprehensive statement by expert group from GCC region

BReast CAncer (BRCA)1 and BRCA2 gene pathogenic variants account for most hereditary breast cancers (BC). Identification of BRCA mutations can significantly influence both prognosis and treatment outcomes. Furthermore, it enables the identification of individuals who are at heightened risk of developing BC due to inherited genetic mutations. Many developing countries rely on western guidelines for BRCA testing and BC management; however, there exist wide disparities in the prevalence of risk factors, availability of medical resources, and practice patterns. Guidelines tailored to specific regions can help mitigate healthcare variations, promote consistency in treatment, and aid healthcare providers in identifying effective therapies for improving patient outcomes. Hence, oncologists from the Gulf Cooperation Council (GCC) congregated virtually in March 2023 and reviewed existing data on the epidemiology of BC, BRCA mutations, practices and challenges associated with BRCA testing and management of BRCA mutated early-stage BC in the GCC region. They also provided insights on the real-world diagnostic and treatment practices and challenges in the GCC region in the BRCA-mutated early-stage BC domain and suggested some variations to international guidelines to aid their uptake in this region.


Introduction
Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women in the Gulf Cooperation Council (GCC) region, with an age-standardized incidence rate of 34.4 per 100 000 and a mortality rate of 10.6 per 100 000 in 2020 (Supplementary Table S1) (1).In most GCC countries, the incidence of BC has increased over time among women (2).Hereditary factors are responsible for around 10% to 30% of BC cases (3) and 16% of these hereditary cases are related to germline mutations in BReast CAncer gene (BRCA)1 and BRCA2 genes (4).Other factors such as early age menarche, later age at menopause, shorter breastfeeding periods, use of oral contraceptives or hormonal therapy, dense breasts, and older age are found to be associated with increased risk of BC (5,6).
Outcomes in BC depend primarily on timely diagnosis and access to appropriate treatment.Patients who are diagnosed at the early stages (stage 0, I, II) tend to have higher overall survival (OS) rates than people diagnosed with stage III or IV BC (14); the 5-year survival rate reported for women with stage I BC was found to be 99% and the same for patients with stage II BC was 86% (14).The 5year survival rate in the GCC region ranges between 63% and 89%, with the highest 5-year survival rate being reported in the United Arab Emirates (UAE) and the least being reported in Bahrain (15)(16)(17).The cumulative risk for developing BC by age 70 years was 65% for BRCA1 carriers and 45% for BRCA2 carriers (18).Identification of BRCA mutation in a woman diagnosed with BC may have an impact on both prognosis and treatment (19)-especially it influences the extent of surgery such as the choice of breastconserving surgery (BCS) or contralateral mastectomy, also predicts the effectiveness of platinum-based chemotherapy (20) and poly (ADP-ribose) polymerase (PARP) inhibitors (21).Moreover, it facilitates the identification of individuals who are at high risk of BC due to hereditary genetic mutations.This knowledge can help with making decisions regarding risk-reducing measures such as enhanced surveillance, prophylactic surgery, and chemoprevention.Although most developing countries lean on western guidelines for the management of BC, there are wide differences in the prevalence of risk factors, availability of medical resources, and practice patterns.Region-specific guidelines can curb healthcare variations, drive consistency in delivery, and help healthcare providers navigate effective therapies for improving patient outcomes.Hence, this expert opinion paper intends to provide data on the epidemiology of BC, BRCA mutations, practices, and challenges associated with BRCA testing in the GCC region.It will also provide recommendations for the BRCA testing and management of BRCA-mutated early-stage BC.

Methodology
A multidisciplinary panel of 9 oncologists, experts in BC, from 4 different GCC countries (Kuwait [n=1], Kingdom Saudi Arabia (KSA) [n=3], Qatar [n=1], and UAE [n=4]) congregated virtually in March 2023 to discuss gaps observed in the clinical practice and treatment goals in patients with BRCA mutated early-stage BC in GCC region.The aim was to gain insights into the evolving treatment paradigm in germline BRCA-mutated early-stage BC.The panel discussed the available data on disease burden, BRCA mutations (BRCAm), BRCA testing, and management practices along with associated challenges specific to their region.They provided strategic as well as implementable recommendations to enhance BRCA testing in early-stage BC in the GCC region.Additionally, members of the panel also provided recommendations for developing a treatment algorithm for BRCA-mutated early-stage BC.We present an expert opinion manuscript with recommendations for the BRCA testing and management of BRCA mutated early-stage BC in GCC, based on the published literature and expert clinical opinion.All the experts critically reviewed, revised, and approved the manuscript draft.
A meta-analysis demonstrated a significantly higher risk for ipsilateral breast recurrence (IBR) in BCRA1/2 mutation carriers compared to non-carriers following BCS at a median follow-up ≥7 years (30).Contralateral BC is more often observed in BRCAmutated BC than in sporadic BC (31).Several studies demonstrated that BRCA-mutated BC has worse OS (32) and BC-specific survival (BCSS) than sporadic/BRCA-negative cases (33).
Emerging research on BC demonstrates that BRCA status predicts sensitivity to platinum-based chemotherapy (20), and PARP inhibitors (21), owing to the ability of these drugs to inhibit deoxyribonucleic acid (DNA) repair pathways.Evaluation of BRCA1/2 mutational status (33) in patients with BC helps to potentially expand treatment options, implement prevention strategies, and improve survival outcomes (34).

Epidemiology and prevalence of BRCA mutations in GCC
Except for Kuwait, the prevalence of a germline BRCAm in GCC countries ranges from 10% to 12% in unselected BC patient populations (35-38).In Kuwait germline BRCA1 mutation prevalence rate was reported as 21% (39).However, this finding in Kuwait could be due to a small sample size and selection bias; it should not be considered robust enough to affect the clinical practice.BRCA mutation prevalence is higher in patients with a family history of BC diagnosed at a young age or a family history of ovarian cancer (40).
5 Management of BRCA-mutated early-stage breast cancer 5.1 Role of MDT and genetic counselor

Role of MDT
Multidisciplinary teams (MDT) play a critical role in the early management of BC.The MDT approach is recommended by many international guidelines (41,42).
MDT approach presents a significant impact on patient management (43).Patients discussed at MDT meetings are more likely to receive more accurate as well as complete pre-operative staging, and neo-adjuvant/adjuvant treatment (44).MDT care can intercept 98.8% of all medication errors, thereby improving the quality of care (45).In women with early BC, it has the potential to improve quality of life, reduce mortality, and reduce healthcare costs (46).Studies have reported that patients who are managed by MDTs have improved survival outcomes (47) and the relative risk of recurrence (hazard ratio: 0.84; 95% CI, 0.70 to 0.99) and death (hazard ratio: 0.89; 95% CI, 0.82 to 0.96) was significantly decreased compared to those who are not (48).

Role of genetic counselor
A genetic counselor plays a crucial role in early BC management.Genetic counseling before genetic testing is endorsed by many international guidelines (41,42).Genetic counseling has been shown to improve patient outcomes with positive downstream effects as patients are more equipped to share the results of genetic tests with extended families (49).Some key aspects of their role in BC management are illustrated in Supplementary Figure S1.

Diagnostic work up
Breast cancer is commonly diagnosed either through screening or a symptom (e.g., pain or a palpable mass) that prompts a diagnostic examination.Mammography (bilateral) is the standard diagnostic modality for diagnosing BC (41).However, falsenegative mammography results are often observed in some cases.Studies reported that false-negative mammography results are associated with factors such as higher breast tissue density, the presence of BRCA1/2 mutations and, both of which may be more prevalent in younger women (50).In such cases (high-risk patients), augmenting mammography with ultrasound can uncover additional cases of mammographically hidden cancers; the use of magnetic resonance imaging (MRI) is optional.The sensitivity of ultrasound screening appeared to be similar to that of mammography in a population with a high-risk of BC (41,51,52).Breast MRI may be used for staging evaluation to define the extent of cancer, in the adjuvant or neo-adjuvant settings to detect the presence of multifocal or multi-centric cancer in the ipsilateral breast, or as screening of the contralateral BC at the time of initial diagnosis (41).
Routine pathologic evaluation of the primary tumor and cytology/histology of the axillary nodes, if involvement is suspected remains the most critical element in determining the prognosis of patients with BC (53).Pathological diagnosis should be based on a core needle biopsy, preferably obtained by ultrasound or stereotactic guidance (53).Additionally, the analysis of specific biomarkers, such as hormone receptors (estrogen and progesterone receptors) and HER2 are important in guiding targeted therapies (53).HER2 testing is routinely recommended in all cases of invasive BCs (41).

Genetic testing for BRCA mutations
The National Comprehensive Cancer Network ® (NCCN ® ) (54), and several other professional organizations (53,55) recommend genetic testing for patients who are at high risk for harboring a pathogenic mutation in one of the BC-predisposition genes.These organizations have developed criteria based on personal/family history and age of onset of cancer to identify patients at high risk (Table 1) (53)(54)(55)(56)62).The majority of these guidelines are primarily based on the probability of carrying pathogenic mutations in BRCA genes.Some of these guidelines (55) propose the use of screening tools (57-61) to identify a family history associated with an increased risk for potentially harmful mutations in BC-susceptibility genes (BRCA1 or BRCA2).Recent studies indicated that nearly 50% of women with BC with germline predisposing mutations are missed by current testing criteria (63).Furthermore, family history-based criteria have limited pertinency in patients who are adopted or unaware of the family history of cancer or have limited family structure (64).Studies on universal testing indicate that guidelines should be broadened to encompass testing of all patients diagnosed with BC (65-67).Researchers report that universal genetic testing after BC diagnosis can uncover clinically significant germline pathogenic variants that might otherwise escape detection due to narrow selection criteria as per current testing guidelines (66).
Referral to a Specialist Genetic Clinic •→ An individual with the following family history of female BC: o→ Two first-degree or second-degree relatives diagnosed with BC at a younger age <50 years (at least one must be a first-degree relative) o→ Three firstor second-degree relatives diagnosed with BC at younger age <60 years (at least one must be a firstdegree relative) o→ Four relatives diagnosed with BC at any age (at least one must be a first-degree relative) •→ Families containing one relative with ovarian cancer at any age and on the same side of the family: •→ Women with a family history of breast, ovarian, tubal, or peritoneal cancer.Screening can be done using one of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in BC-susceptibility genes (BRCA1 or BRCA2).
•→ Genetic testing should be available to all patients with a personal history of BC. •→ Patients who had genetic testing previously may benefit from updated testing for PALB2, genomic rearrangements in BRCA1/2, and other potentially relevant genes, if not performed already.•→ Genetic testing should be made available to patients without a history of BC who meet NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ).
ASBrS, American Society of Breast Surgeons; BC, breast cancer; NCCN=National Comprehensive Cancer Network ® (NCCN ® ); NICE, National Institute of Clinical Excellence; TNBC, triple-negative breast cancer; USPSTF, U.S. Preventive Service Task Force.*Each risk assessment tool has its own strengths and weaknesses; clinicians should be aware of these before use.†Cancer of the peritoneum and fallopian tubes should be considered a part of the spectrum of hereditary breast and ovarian cancer syndrome.
† †Close relative is defined as a first−degree relative (mother, sister, daughter) or second −degree relative (grandmother, granddaughter, aunt, niece).
BRCA1 and BRCA2 gene mutations account for most actionable genetic BC predispositions and are increasingly used for personalized BC management and PARP inhibitors therapy of BRCA-related cancer (68).BRCA1 and BRCA2 mutations are found to be associated with a younger age of onset (25).Also, in GCC countries, the mean age at diagnosis was less than 48 years (with 69% of cases between 25-54 years) (7,13).Thus, the experts have proposed the criteria mentioned in Box 1 for BRCA testing.
Research investigating next-generation sequencing workflows for BRCA1/2 genes in samples associated with hereditary breast and ovarian cancer has shown outstanding performance, achieving nearly 100% sensitivity and specificity, while also proving to be cost-effective when compared to single-site mutation testing specifically for these genes (69).
Diagnostic laboratories have identified numerous variants of uncertain (or unknown) significance (VUS) in the BRCA1 and BRCA2 genes, owing to their large size and the extensive screening conducted on them.One study reported a VUS frequency rate for BRCA1 and BRCA2 of 13% for 10,000 consecutive individuals (70).Studies from the GCC region reported a high rate of VUS ranging from 14.5% to 25.4% (36, 38).However, initiatives to reclassify BRCA VUS are likely to reduce this number (71).Evaluating a VUS in BRCA genes is a complex undertaking, but it is reported that VUS can be characterized by gathering evidence from databases that document well-characterized populations, and in silico assessment (71).

Impact of timing of genetic testing on surgical decision
Traditionally, BRCA testing is conducted after primary surgery for BC; later once testing results are available, patients identified with BRCA mutations undergo a second breast surgery/bilateral salpingooophorectomy for risk reduction.Recent advancements in genetic testing have significantly reduced turnaround time for BRCA1/2 mutation tests.This has allowed patients to undergo genetic testing without the need to delay treatment.Consequently, integration of test results into management decisions can now be seamlessly achieved at the time of diagnosis.This may eliminate the requirement for a second breast surgery for risk reduction, as some women diagnosed with deleterious mutations choose to concurrently undergo therapeutic surgery for the affected breast and risk-reducing surgery for the contralateral breast.
Studies indicated that genetic diagnosis before surgery has an impact on the surgical decision, choosing unilateral mastectomy or bilateral mastectomy in BRCA mutation carriers with BC (72).A study conducted on patients with unilateral BC reported that only 14.7% of patients with unknown BRCA mutation status before surgery received contralateral mastectomy in contrast to 76.4% of patients who underwent contralateral prophylactic mastectomy with BRCA mutation status known preoperatively.These data support preoperative genetic testing for BRCA mutation in patients with newly diagnosed BC to enable appropriate planning of surgical treatment decisions (73).Hence, providing genetic counseling and BRCA testing before surgical approach and developing treatment strategies for patients with a high risk of BC is important (72).

Current BRCA testing landscape, challenges, and expert recommendations for improving
In the GCC region, there are variations in practices for BRCA testing.Currently, few accredited loco-regional laboratories perform BRCA testing.In most countries limited number of cancer centers have a dedicated genetic counselor; counseling is often provided by the medical oncologist, with evident variations in skills and knowledge in this niche area of expertise.Financial support for BRCA testing is provided by pharmaceutical companies.In this region, very few patients are referred for BRCA testing, particularly in government hospitals because most patients neither have insurance nor are willing to pay for the test and the referral is left at the discretion of individual physicians, surgeons, oncologists, and finally patients, which causes inconsistency of BRCA testing.This has resulted in the lack of a regional integrated genetic database.In government hospitals, there are constraints concerning indications, the budget, and a long waiting list for performing screening tests.However, in private institutions, BRCA testing is being endorsed for almost all or high-risk BC patients who have insurance or are willing to pay for the tests.In some countries, genetic testing is often excluded from health insurance policies, making it difficult for patients with cancer to access this crucial service.At present, there are no region-specific genetic testing algorithms or guidelines that regulate BRCA testing in the GCC region.Currently, NCCN Guidelines ® (41) are followed for recommending germline BRCA testing.Universal genome testing (wherever possible) or BRCA testing for an extended population with indications beyond those in the guidelines is advised by the majority of experts considering the treatment-related benefits of BRCA testing and it is implemented in some centers in the GCC, yet we believe there are few centers offering universal testing.
A correspondence article published in 2016 reported that in GCC, most molecular diagnostic samples were sent to Western countries for testing and analysis, and the results from a significant amount of these samples came back negative or inconclusive (74).This finding warrants an immediate need to establish accredited molecular diagnostics locally to customize the molecular genetic approaches.Real-world data have suggested a significant deficit in physician-driven referrals for BRCA testing in guideline-eligible BC patients primarily due to a lack of access and knowledge about the criteria for testing (75).Less than 60% of guideline-eligible patients with BC received BRCA testing in the United States of America (USA) and European countries (75, 76).In contrast, 97% of guideline-eligible BC patients received BRCA testing in Israel (76).Lack of knowledge among community oncologists/surgeons about the selection criteria is one of the important barriers for implementing BRCA testing in the GCC region.Expert recommendations for BRCA testing and for supportive measures for improving BRCA testing in the GCC region are present in Box 1.1 and Box 1.2.

Treatment
Treatment of BRCA mutated early-stage BC is complex and involves the combination of local modalities, and systemic anticancer treatments delivered in diverse sequences.

Surgery
Breast-conserving surgery or mastectomy are the primary treatment options for patients with BRCA mutated early BC (77), similar to sporadic BC (53).The choice of surgery depends on factors such as age, tumor size, location, TNM stage, and patient preferences (77).BCS is the optimal surgical choice when the tumor is small and is localized to one part of the breast (53).Mastectomy is indicated for the patients who choose to undergo this procedure over BCS or where there is an inability to achieve negative surgical margins after multiple resections or received prior radiation to the chest wall/breast or other contraindications to radiotherapy (RT) (41).Retrospective studies that evaluated long-term outcomes in BRCA1/2 carriers have found no significant difference in RFS, breast cancer-specific survival (BCSS), or OS, between BCS and mastectomy; however, an increased risk of local recurrence was reported for BCS (78-81).Similar findings were reported in a systematic review by Co et al. (77), that compared survival outcomes and recurrence rates between BRCA mutation carriers who received BCS and those who received mastectomy.Overview of studies that evaluated BCS and mastectomy in early-stage BC patients with BRCA mutations are presented in Supplementary Table S2 (77)(78)(79)(80)(81). Based on the available evidence, the researchers have indicated that BCS could be a good choice for BRCA mutation carriers, as long as they receive appropriate counseling and have rigorous follow-up (77).
Gentile et al, suggested that young BRCA-mutated patients with small tumors may not need an up-front mastectomy (82).Although data from the Danish Breast Cancer Group, reported a reduced risk of death for risk-reducing contralateral mastectomy (RRCM) (adjusted OS hazard ratio: 0.42, p=0.01) (83).A systematic review and meta-analysis by Fayanju et al. reported that RRCM may not necessarily result in improvement of OS, despite reducing the risk of contralateral BC (84).Limited data are available on the survival impact of RRCM in BRCA mutated patients with unilateral BC.For patients who require a mastectomy, breast reconstruction (immediate or delayed) could be an option (53).The nipple-BOX 1.1 Expert recommendations for BRCA testing in the GCC region.
-Genetic counseling and testing for germline BRCA1 and BRCA2 mutations should be indicated in the following scenarios: Individual (BC) -Age less than or equal to 50 years -Triple-negative BC at any age -Bilateral BC at any age -HR-positive BC with N2 disease at any age -BC with Ashkenazi Jewish or Icelandic heritages -Any patient who is eligible for adjuvant PARP inhibitor -Male BC Positive family history is defined as below: -≥1 close blood relatives with BC at age ≤ 50 -≥1 close blood relative with male BC -≥1 case of a blood relative with ovarian cancer -≥1 case of a blood relative with pancreatic cancer -≥1 case of a blood relative with prostate cancer with metastatic, or high-or very-high-risk group -≥3 diagnoses of breast or prostate cancer (any grade) on the same side of the family including the patient with BC -Individuals affected with BC (not meeting testing criteria listed above) or individual unaffected with BC with a firstor second-degree blood relative meeting any of the criteria listed above BC, Breast cancer; BRCA, BReast CAncer gene; HR, Hormone receptor; PARP, poly-ADP ribose polymerase BOX 1.2 Expert recommendations for supportive measures for improving BRCA testing in the GCC region.
▪ Need refined definitive region-specific guidelines for BRCA testing ▪ Raise awareness among community oncologists/surgeons about the selection criteria for BRCA testing ▪ Increased access to testing would likely lead to more patients pursuing testing and improving rates of identification of gene carriers ▪ All institutions should have access to genetic counselors who are experienced in counseling patients with BC ▪ Regulators and stakeholders should work to make BRCA testing widely available and accessible for BC patients ▪ Systematically discuss the cases of variants of unknown significant mutations with a genetic counselor in an MDT approach ▪ For patients with VUS, genetic counselors need to follow up with the patients to check if they develop any other cancer in their family ▪ Create a database for BRCA variants and BRCA pathogenic variants and compare it with the global data ▪ There is an urgent need for extensive, well-controlled, genetic epidemiological studies to provide accurate BRCA1 and BRCA2 mutation prevalence among patients with BC in the GCC region ▪ Establish a centralized laboratory that provides free BRCA tests and delivers timely test results without discrepancies ▪ It is recommended to make BRCA testing available for all patients whenever possible.An approach to generalize BRCA testing to the general population with BC instead of restricting it to only a group of patients with BC (per the selective criteria) to provide more treatment benefits.BC, Breast cancer; BRCA, BReast CAncer gene; GCC, Gulf Cooperation Council; MDT, multidisciplinary team; TNBC, Triple-negative breast cancer; VUS, variants of unknown significance sparing mastectomy has proven to be safe in patients carrying BRCA mutations, as both a therapeutic option and in terms of riskreduction, due to its minimal local recurrence rates compared to a modified radical mastectomy (53,85), although more data and longer follow-up are needed.

Radiotherapy
A meta-analysis on randomized controlled clinical trials (RCTs) demonstrated a significant reduction in the 10-year risk of recurrence (absolute reduction 15.7%, 95% CI 13.7-17.7,2p<0.00001) and 15-year risk of BC death (absolute reduction 3.8%, 1.6-6.0,2p=0.00005) in patients with early BC who received whole breast irradiation after BCS compared with those who received BCS alone (86).Researchers reported that tumors harboring BRCA mutations could be sensitive to RT, because ionizing radiation has the ability to induce double standard breaks (DNBs) in DNA, and BRCA genes play a key role in repairing such DNBs (68).Multiple studies have reported that the risk of local recurrence after BCS and RT is comparable between patients with BRCA-mutated BC and those with sporadic BC (22,87,88).Similarly, studies have proven the equivalence in the survival of patients with BRCA mutations between BCS with RT vs mastectomy (78) or BCS vs mastectomy with RT (81).No evidence of impaired survival and toxicity related to irradiation has been observed in patients with BRCA mutations, suggesting that RT may be safe in these patients and should not be withheld (89,90).Pierce et al (78) compared 10-year rates of IBTR/events after BCS and RT among BRCA1/2 mutation carriers and women with sporadic BC and found no statistically significant difference.An overview of studies that evaluated adjuvant RT efficacy in BC patients with BRCA mutations is presented in Supplementary Table S3 (78, 81, 87-89).

Chemotherapy
Chemotherapy is recommended in the vast majority of TNBC, HER2-positive BC, and in high-risk luminal-like HER2-negative BC (53).The most frequently used regimen includes taxanes and/or anthracyclines but in selected patients, cyclophosphamide/5fluorouracil (5-FU)/methotrexate may still be used (53).The taxanes, namely paclitaxel and docetaxel, play a significant role in the therapeutic management of BC.Patients with hormone receptor (HR) negative BC carrying BRCA1 mutations exhibited less sensitivity to taxane chemotherapy than non-BRCA1 mutation carriers with HR negative BC (91).Conversely, in patients with HR-positive BC with BRCA1 and BRCA2 mutations and sporadic cases, similar sensitivities were reported with taxane therapy (91).In the Arun et al. study, BRCA1 mutation carriers showed higher pathological complete response (pCR) (46% vs 22%) compared to patients with sporadic BC, when treated with the combination of anthracycline-taxane, in neoadjuvant settings (92).Multiple studies have indicated that BRCA1/2 mutation carriers are more prone to exhibiting a favorable response to neoadjuvant anthracycline-based regimens (92-94) or single-agent cisplatin (95), as evidenced by a higher rate of achieving pCR.In the INFORM trial, neoadjuvant single-agent cisplatin did not yield superior pCR rates when c o m p a r e d t o t h e c o m b i n a t i o n o f d o x o r u b i c i n a n d cyclophosphamide in patients with HER2 negative early BC who carry BRCA1/2 mutations (96).In the TNT trial carboplatin demonstrated a markedly greater response in patients with BRCA mutated and TNBC as compared to docetaxel (20).
Studies that explored the utilization of platinum agents in neoadjuvant settings in patients with BRCA-mutated early-stage TNBC demonstrated high pCR rates with the addition of platinum agents to standard chemotherapy regimens (anthracycline, cyclophosphamide, taxanes) (97-99).Zang et al., reported improved recurrence-free survival (RFS) and OS rates among BRCA1/2-mutated TNBC patients when carboplatin is added to standard anthracycline-taxane-based neoadjuvant chemotherapy (NACT) (100).On the contrary, in the GeparSixto trial and Brightness trial no additional benefit was observed in patients with BRCA-mutated TNBC with the addition of a platinum agent (carboplatin) to NACT (99,101).An overview of studies that evaluated chemotherapy efficacy in BC patients with BRCA mutations are presented in Supplementary Table S4 (91, 92, 94, 99-101).

Endocrine therapy
Endocrine therapy (ET) is a common treatment option for early-stage BC.It is often used as adjuvant therapy after surgery to reduce the risk of BC recurrence, or as neoadjuvant therapy to shrink the tumor before surgery (53).Adjuvant tamoxifen (given for 5 years) showed a 31% decrease in mortality rate from BC in patients with estrogen receptor (ER)-positive BC and proved to be superior to 1 or 2 years of tamoxifen treatment (102).However, in patients with a BRCA-mutated HR-positive BC, ET exhibited a lower survival rate in comparison to their counterparts who do not possess the BRCA mutation (103).Empirical evidence indicates that tamoxifen use is associated with a reduction in contralateral BC risk among BRCA mutation carriers (104, 105), with a suggested influence on both ER-positive and -negative disease.

Poly(ADP-ribose) polymerase inhibitors
With the promising results for PARP inhibitors (Olaparib, talazoparib) in the treatment of BRCA-mutated BC in metastatic/ advanced settings (108, 109), clinical trials are investigating their potential role in early-stage disease, as monotherapy or with other cytotoxic agents or with immunotherapy in neoadjuvant and adjuvant settings.Currently, the PARP inhibitor, olaparib is approved for the adjuvant treatment of adult patients with germline BRCA-mutated HER2-negative high-risk early BC who have been treated with neoadjuvant or adjuvant chemotherapy based on the results of the OlympiA trial (110,111).
OlympiA was a double-blinded, phase III trial conducted to evaluate the safety and efficacy of adjuvant olaparib therapy versus placebo in high-risk, germline BRCA-mutated, HER2-negative early BC who received local treatment and neoadjuvant or adjuvant chemotherapy (at least 6 cycles anthracyclines or/and taxanes.OlympiA examined four patient populations considered to have HER2-negative disease at high risk of recurrence, and inclusion criteria varied based on tumor subtype and therapy setting (Table 2) (111).
At the initial interim analysis (111), a significant decrease in the disease recurrence or death was observed with the use of olaparib, successfully achieving the primary objective of the study (hazard ratio 0.58; p<0.001).In the second-interim analysis, a statistically significant and clinically meaningful improvement in OS was observed with olaparib compared with placebo (hazard ratio: 0.68; p=0.009) with an absolute improvement in 4-year OS of 3.4% (89.8% olaparib; 86.4% placebo) (112).The survival benefit of olaparib was observed irrespective of germline BRCA status, HR status, prior platinum use, and adjuvant chemotherapy or NACT (112).The international guidelines have updated their BC treatment guidelines to include treatment with the PARP inhibitor olaparib for one year after completing chemotherapy, surgery, and radiation (if used) to improve outcomes in patients with an inherited mutation in BRCA1/2 with early-stage, HER2-negative BC who have a high risk for recurrence (113).
In the phase II study, talazoparib monotherapy elicited pCR rates that were comparable to those observed with combination anthracycline and taxane-based chemotherapy regimens when used in the neoadjuvant settings in patients with BRCA1/2 positive, early HER2-negative BC (114).In the phase II single-arm NEOTALA trial, talazoparib yielded promising pCR rates in patients with BRCA mutated early BC comparable to those historically observed with combination anthracycline-and taxane-based chemotherapy regimens (115).

Combination of PARP inhibitors and immunotherapy agents
Multiple clinical trials have assessed the efficacy of combining PARP inhibitors and immune checkpoint inhibitors (ICIs) in the context of metastatic cancer.These trials include MEDIOLA (118), TOPACIO (119), KEYLYNK-007 (120), and JAVELIN PARP Medley (121).The results of these trials have demonstrated a favorable toxicity profile for pembrolizumab (119,120), durvalumab (118), and avelumab (121).The combination of PARP inhibitors and ICIs may emerge as a promising therapeutic strategy for patients harboring BRCA mutations.These tumors appear as more immunogenic due to their higher levels of tumorinfiltrating lymphocytes, higher mutational burden, and expression of immune checkpoint inhibitory molecules compared to BCs without BRCA mutations.Encouraged by results for ICIs from the metastatic setting, ICIs are now being assessed for the treatment of advanced mutated BC and early-stage BC with BRCA mutations (DORA trial, DOLAF, KEYLYNK trial, NCT03329937, NCT03150576, and NCT03499353).
In the phase II ISPY-2 trial, neoadjuvant durvalumab and olaparib exhibited superior efficacy in terms of pCR over standard NACT in HER2-negative BC, particularly in a highly sensitive subset of high-risk HR-positive, HER2-negative patients (64% vs 22%) (122).Although it remains uncertain whether the incorporation of immunotherapy alongside PARP inhibitors yields superior outcomes in comparison to single-agent PARP inhibitors, safety data obtained in the metastatic context indicate that the combination is welltolerated.Despite the lack of empirical evidence, data extrapolation consequently advocates for the co-administration of adjuvant pembrolizumab and olaparib in high-risk patients with residual disease following chemo-immunotherapy.
6 Healthcare infrastructure in the GCC region for managing BRCAmutated early-stage BC In recent years, GCC countries have made significant progress in enhancing the healthcare infrastructure for BC management.

HER2 negative disease
Prior therapy High-risk criteria  (126).In UAE, several general oncology care services have been initiated across the nation to enable cancer patients to access healthcare facilities closer to their homes (125).In Kuwait and Bahrain, all the general hospitals are equipped with a radiology department along with molecular imaging and nuclear medicine (123, 124).In UAE, radiotherapy facilities are located across the country and offer advanced treatment options (125).
Besides in countries like KSA, UAE and Qatar, cancer care is provided free of charge to all their citizens through health insurance and non-profit organizations to non-citizens (125,126,128).Such care includes laboratory tests, clinical imaging, systemic anti-cancer therapies, surgery, and radiotherapy.Bahraini citizens, on the other 7 Challenges in management of BRCA-mutated early-stage BC Limited availability of specialized BC centers and oncology services in certain GCC countries can impede timely access to comprehensive care, including diagnosis, treatment, and support services.Within GCC countries, geographic disparities in healthcare infrastructure and resources may result in unequal access to BC care, especially for patients residing in remote or rural areas far from major healthcare facilities.In most GCC countries patients have access to all historically used drugs; however, there is a wide disparity in accessing novel targeted therapies such as abemaciclib olaparib, and talazoparib due to lack of approval or non-reimbursement, or high costs.For example, in UAE and Saudi Arabia, drugs like abemaciclib, olaparib are approved for BRCA mutated BC (7).However, in countries like Kuwait they are not accessible yet for management of early-stage BC.Hence, governments may need to take efforts to ensure that novel drugs are readily available to patients from these countries.
Financial barriers, such as high treatment costs, insurance limitations, and out-of-pocket expenses, may present challenges for patients, particularly non-citizens and those without sufficient insurance coverage, despite efforts to provide free or subsidized cancer care for citizens.Besides, patient factors such as adherence to treatment protocols, including medication regimens and follow-up appointments, can be difficult due to factors such as treatmentrelated side effects, logistical challenges, and cultural beliefs about illness and treatment.Cultural beliefs and social stigma surrounding cancer, specifically BC, can influence patient decision-making, treatment-seeking behavior, and disclosure of diagnosis.Fear, misconceptions, and cultural taboos may contribute to delayed presentation, reluctance to seek medical help, and adherence issues.Gender norms and cultural expectations regarding women's roles and health-seeking behavior can impact access to BC care.Cultural factors related to modesty, privacy concerns, and family dynamics may affect women's ability to access screening services, discuss symptoms, and seek timely medical care.
Thus, it is imperative to increase awareness among people toward BC, genetic testing, and advocacy for insurance coverage.Additionally providing support services to promote treatment adherence and address psychosocial needs is essential.

Conclusion
BRCA testing is an important and critical diagnostic tool in the early-stage BC care as it enables personalized treatment plans to improve patient outcomes.With continued advancements in research and technology, the role of BRCA testing in the management of BC is likely to expand further, offering new opportunities for early detection, risk reduction, and personalized care for patients with BRCA-mutated BC.With the availability of BOX 2 Panel recommendations for the management of early BC in Germline BRCA carriers.
▪ BCS is the preferred local treatment option for the majority of BRCA-mutated early BC patients, with the use of oncoplastic techniques, to maintain good cosmetic outcomes in technically challenging cases, when needed.▪ After surgical resection, careful assessment of resection margins is essential.No tumor at the inked margin is recommended for either in situ disease or invasive BCs and >2 mm for in situ disease is recommended (41).▪ Prophylactic contralateral mastectomy should be considered for patients with a very early disease with T0, T1, or M0 with germline BRCA mutations.▪ Breast reconstruction should be available and proposed to all women requiring mastectomy.Immediate breast reconstruction should be offered to the vast majority of patients, except for those presenting with inflammatory cancer.▪ The optimal reconstruction technique for each patient should be discussed individually taking into account anatomic, treatment and patient-related factors and preferences.▪ Postoperative RT is strongly recommended after BCS.Post-mastectomy RT is recommended for high-risk patients, including those with involved resection margins, involved axillary lymph nodes and T3-T4 tumors; it should also be considered in patients with 1-3 positive axillary lymph nodes.▪ Patients fulfilling the OlympiA criteria are considered high-risk patients for recurrence.▪ The panel recommends offering 1-year of adjuvant olaparib for patients with high-risk, early-stage HER2-negative BC with germline BRCA mutations after completion of neoadjuvant chemotherapy and local treatment, including radiation.▪ In patients with TNBC with germline BRCA mutations and PDL1 expression who did not achieve pCR with neoadjuvant treatment, a combination of pembrolizumab with olaparib is recommended.However, there is no clinical evidence to support the recommendation.BC, Breast cancer; BCS, Breast conservative surgery; BRCA, BReast CAncer gene; HER2, Human epidermal growth factor receptor 2; pCR, pathologic complete response; RT, Radiotherapy.

8
Expert panel recommendations for the management of BRCA mutated early BC in germline BRCA carriers Expert panel recommendations for the management of early BC are presented in Box 2 and the treatment algorithms are presented in Figure 1 (129).
Al-Shamsi et al.10.3389/fonc.2024.1358982Frontiers in Oncology frontiersin.orgcomprehensive and cost-effective genetic testing for germline BRCA1/2 mutations and the valuable information it provides for treatment options, it may be reasonable to consider BRCA testing beyond previously established selection criteria.The inclusion of olaparib as an adjuvant therapy for early BC patients with BRCA mutations marks a significant advancement in the treatment of this patient population.It is imperative for surgical/medical oncologists to consider it in the locoregional systemic management of early BC for improved patient outcomes.

TABLE 1
International guidelines recommendations for genetic or BRCA1/2 testing.Diagnosis of BC before the age of 50 years •→ Diagnosis of TNBC before the age of 60 years •→ Personal history of ovarian cancer or second BC or -TNBC -Multiple primary BCs (synchronous or metachronous) -Lobular BC with a personal or family history of diffuse gastric cancer ▪→ Male BC ▪→ Ashkenazi Jewish ancestry ▪→ Family history -≥1 close blood relative with ANY: o→ BC at age ≤50 years o→ male BC o→ ovarian cancer o→ pancreatic cancer o→ prostate cancer with metastatic, or high-or very-high-risk group -≥3 total diagnoses of BC in patient and/or close blood relatives -Individuals affected with breast cancer (not meeting testing criteria listed above) or individual unaffected with breast cancer with a firstor second-degree blood relative meeting any of the criteria listed above ESMO, 2019(53)•→ Strong family history of breast, ovarian, pancreatic and/or high-grade/metastatic prostate cancer •→

TABLE 1 Continued
Guidelines Recommendations for testing high-penetrance breast cancer susceptibility genes (including BRCA1/2) o→ One first-degree relative (including the relative with ovarian cancer) or second-degree relative diagnosed with BC at younger than age 50 years o→ Two first-degree or second-degree relatives diagnosed with BC at younger than the average age of 60 years o→ Another ovarian cancer at any age •→ Families affected by bilateral cancer (each BC has the same count value as one relative): o→ One first-degree relative with cancer diagnosed in both breasts at a younger age (<50 years) o→ One first-degree or second-degree relative was diagnosed with bilateral cancer and one firstor seconddegree relative or diagnosed with BC at a younger age (<60 years) •→ Families containing male BC at any age and, on the same side of the family, at least: o→ One first-degree or second-degree relative diagnosed with BC at a younger age <50 years o→ Two first-degree or second-degree relatives diagnosed with BC at a younger age <60 years •→ A formal risk assessment has given risk estimates of: o→ 10% or greater chance of a gene mutation being harbored in the family o→ Greater than 8% risk for developing BC in the next 10 years o→ 30% or greater lifetime risk for developing BC USPSTF, 2019

TABLE 3
Clinical trials of oral PARP inhibitors for early-stage breast cancer in the neoadjuvant/adjuvant settings., receive free treatment at public hospitals.Most GCC nations provide an extensive array of treatment choices such as surgery, chemotherapy, radiation therapy, hormone therapy and targeted therapy guaranteeing individualized and efficient healthcare for patients (123-127).