Recommendations for Advancing the Diagnosis and Management of Hereditary Breast and Ovarian Cancer in Brazil

Recommendations for Advancing the Diagnosis and Management of Hereditary Breast and Ovarian... special articles abstract Recommendations for Advancing the Diagnosis and Management of Hereditary Breast and Ovarian Cancer in Brazil 1 2 3,4 5,6 Maria Isabel Achatz, MD, PhD ; Maira Caleffi, MD, PhD ; Rodrigo Guindalini, MD, PhD ; Renato Moretti Marques, PhD ; 7,8,9 10,11 Angelica Nogueira-Rodrigues, PhD ; and Patricia Ashton-Prolla, MD, PhD PURPOSE The objective of this review was to address the barriers limiting access to genetic cancer risk as- sessment and genetic testing for individuals with suspected hereditary breast and ovarian cancer (HBOC) through a review of the diagnosis and management steps of HBOC. METHODS A selected panel of Brazilian experts in fields related to HBOC was provided with a series of relevant questions to address before the multiday conference. During this conference, each narrative was discussed and edited by the entire group, through numerous drafts and rounds of discussion, until a consensus was achieved. RESULTS The authors propose specific and realistic recommendations for improving access to early diagnosis, risk management, and cancer care of HBOC specific to Brazil. Moreover, in creating these recommendations, the authors strived to address all the barriers and impediments mentioned in this article. CONCLUSION There is a great need to expand hereditary cancer testing and counseling in Brazil, and changing current policies is essential to accomplishing this goal. Increased knowledge and awareness, together with regulatory actions to increase access to this technology, have the potential to improve patient care and pre- vention and treatment efforts for patients with cancer across the country. JCO Global Oncol 6:439-452. © 2020 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION panel to address. A written response to each question was drafted by each expert and was discussed during Approximately 10% and 25% of all breast (BC) and 1 a multiday meeting. Questions were edited by the ovarian cancers (OC), respectively, are hereditary. entire group, through numerous drafts and rounds of Identification of pathogenic germline variants in discussion, until complete consensus was obtained. high-/moderate-penetrance cancer-predisposing genes allows the implementation of strategies for cancer risk BURDEN AND EPIDEMIOLOGY OF, AND RISK FACTORS reduction and early detection. In Brazil, there is limited FOR, HBOC access to cancer risk assessment and genetic testing HBOC is a highly penetrant, autosomal dominant for individuals with suspected hereditary cancer, as disorder mostly caused by pathogenic and likely well as limited information on its burden in the country. pathogenic germline variants in BRCA1 and BRCA2 Therefore, the objective of this study was to make ASSOCIATED genes. BRCA1 and BRCA2 are tumor suppres- CONTENT harmonized recommendations for improving early sor genes that repair double-stranded DNA breaks Appendix detection, risk management, and cancer care of through homologous recombination (HR). Individuals Author affiliations patients with hereditary breast and ovarian cancer harboring germline pathogenic variants in BRCA1 and and support (HBOC). BRCA2 are predisposed to BC (lifetime risk up to information (if applicable) appear at 85% and 45%, respectively) and OC (lifetime risk up to METHODOLOGY the end of this 39% and 11%, respectively), as well as other The Americas Health Foundation convened a 6- article. 3-5 malignancies. member panel of clinical and scientific experts in Accepted on January 21, 2020 and oncology, gynecology, genetics, and applied genomics The population prevalence of BRCA1 and BRCA2 published at from Brazil. PubMed and Embase were used to pathogenic variants is 1:150-1:200 individuals in ascopubs.org/journal/ 6 conduct a literature review and to identify Brazilian North American and European populations. Mutation go on March 10, experts who have published in the field of HBOC since prevalence varies according to ethnicity, the genetic 2020: DOI https://doi. 2012. To better focus the discussion, Americas Health testing criteria used, age at cancer diagnosis, and org/10.1200/JGO.19. 00170 Foundation staff developed specific questions for the family history. The catalog of germline variants in 439 Achatz et al CONTEXT Key Objective How can the diagnosis and management of hereditary breast and ovarian cancer be improved in Brazil? A panel of Brazilian experts proposes recommendations for improving access to early diagnosis, risk management, and cancer care of hereditary breast and ovarian cancer. Knowledge Generated Understanding Brazil’s unique social and structural barriers is crucial to expanding access to genetic cancer risk assessment. Government, medical societies, patient organizations, academic centers, and the private sector should collaborate to create a multistakeholder commission to develop and promote the incorporation of genetic cancer risk assessment. Relevance Increased knowledge and awareness, together with regulatory actions to expand hereditary cancer testing and counseling in Brazil, have the potential to improve the care of patients with cancer and reduce the cancer burden across the country. BRCA genes in different populations should be expanded germline BRCA1/2 variants, such as those described by the and made available in public databases such as ClinVar Consortium of Investigators of Modifiers of BRCA1/2. and BRCA Challenge. Risk-protecting factors (eg, breast feeding in BRCA1 car- riers) and risk-enhancing factors (eg, obesity) have been BC and OC risks may be increased by pathogenic variants identified (Appendix Table A1). Studies on cancer risk in other high-penetrance (TP53, PTEN, STK11, CDH1, and modifiers in Brazilian patients with HBOC are not currently PALB2) and moderate-penetrance (CHEK2, ATM, NF1, available. Such studies are needed to verify whether these RAD51C, RAD51D, and BRIP1) genes. The American cancer risk modifiers have a role in risk management College of Medical Genetics has recognized 25 actionable strategies tailored to Brazil’s admixed population. genes for which there is enough evidence to implement an effective cancer risk-reduction strategy. Cancer risk man- MOLECULAR EPIDEMIOLOGY OF HBOC agement has been implemented in BRCA1 and BRCA2 In the mutational landscape of BRCA1 and BRCA2 variants pathogenic carriers, whereas knowledge about the appro- in. 29,000 families substantial variation in mutation type priate management of carriers with moderate-penetrance 8 and frequency by geographical region and race/ethnicity genes is still limited. was observed. Recurrent germline BRCA variants have Multigene panel testing, including actionable genes related been described in specific populations or geographic re- to BC and OC, may be considered for patients who fulfill the gions, and some are caused by founder effects (Table 1). In clinical criteria for HBOC. Testing only BRCA genes may these situations, mutation-specific screening strategies are miss approximately one-half of the pathogenic germline efficient, such as the 3 BRCA1 and BRCA2 Ashkenazi variants involved in HBOC risk, and next-generation se- 13 founder mutations identified in 2.5% of this population. quencing allows testing genes with clinical usefulness at Nine studies have performed comprehensive BRCA mu- 9,11,12 an affordable cost. Panel testing should be recom- tation testing in 2,090 individuals from high-risk cohorts in 17-25 mended only by trained physicians to ensure adequate Brazil. Mutation prevalence estimates in individuals 26,27 genetic counseling and management. There is no added with clinical criteria are 19%-22%. Approximately value of exome and whole-genome testing in HBOC fam- 5% are large gene rearrangements. Certain variants are ilies, and this should not be recommended. Treatment- specific to Brazilian regions as a result of distinctive pat- 28,29 focused genetic testing (TFGT) and genomic tumor profiling terns of immigration in the past centuries. are currently the gold standard in defining better treatment strategies for tumors such as ovarian serous carcinomas. HEREDITARY BC RELATED TO TP53 GENE This generates an urgent need to provide more effec- In Brazil, a significant percentage of BC burden is conferred tive, timely, and adequate pre- and post-test genetic by Li-Fraumeni syndrome (LFS), because of a founder counseling. mutation, TP53 p.Arg337His (p.R337H)(NC_000017.9: Several genetic and environmental factors can modulate c.1010G.A), present in 0.3% of the southern and the penetrance of germline BRCA1 and BRCA2 pathogenic southeastern populations. LFS has a wide tumor spectrum, variants. Variant location, with the identification of clusters predisposing to premenopausal BC, sarcomas, brain tu- of mutations with differential cancer risks, may be asso- mors, and adrenocortical carcinoma, among other 14 30 ciated with higher BC or OC risks. In addition, several cancers. Strong evidence supports the association genetic variants have been identified in coding and non- between the TP53 germline variant and a worse overall and 31-33 coding regions, which may modulate the penetrance of disease-free survival in BC. In classic LFS, cancer risk 440 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil JCO Global Oncology 441 TABLE 1. Recurrent Pathogenic Variants in Hereditary Breast and Ovarian Cancer Syndrome Identified in Different Countries Continent Country Gene Mutation(s) Confirmed Founder Details First Author Africa Algeria, BRCA1 c.798_799delTT No 22% of BRCA1 mutations in North African families Laraqui Morocco, and Tunisia South Africa No BRCA1 No BRCA2 c.1374delC No 77.8% of mutation carriers had one of the Seymour c.2641G.T c.7934delG 3 Afrikaner founder mutations Americas North Mexico BRCA1 Exon 9-12 del Yes 35% and 29% of the BRCA-associated ovarian Villareal-Garza and breast cancer cases, respectively Canada BRCA1 c.4327C . T c.8537_8538del c.5266dupC Yes BRCA2 Yes Cavallone South Brazil BRCA1 Yes Fernandes Asia Israel BRCA1 c.5266dup Yes Manchanda c.68_69del Yes BRCA2 c.5946del Yes Europe Portugal BRCA2 c.156_157insAlu Yes 37.9% of BRCA2 pathogenic variants in Peixoto Portuguese families Iceland BRCA2 c.771_775del Yes Rafnar Hungary BRCA2 c.9097dup Yes Van der Looij Australia/Oceania Australia BRCA1 c.3331_3334del No Also recurrent in Hispanic populations, Europe, Rebbeck USA, and the UK Australia BRCA2 c.6275_6276del No Also recurrent in the UK, Belgium, Spain, the Rebbeck Netherlands, and North America Achatz et al by age 60 years is 90% in women and 73% in men, information to patients before genetic testing should be with an overall cumulative incidence of 50% by age sought, because there is a limited number of genetic risk 34,35 40 years. The p.R337H TP53 variant confers a life- assessment providers. A streamlined approach may be an time cancer risk that differs from typical DNA-biding effective solution. It relies on substituting traditional pretest domain TP53 pathogenic variants. Carriers have a lifetime genetic counseling with providing information, the graphic/ cancer risk of 80% in females, and 47% in males. BC is visual information to the patient, or focused counseling by 43-45 the most common malignancy diagnosed in LFS. In the treating physician. p.R337H carriers, the mean age is 40 years, and in classic UNDERSTANDING GENETIC TESTING RESULTS LFS, 32 years. In a cohort of 815 women affected by BC in In the presence of germline BRCA1/BRCA2 and TP53 southern Brazil who developed the disease before age variants, current options for risk reduction and early de- 45 years, the result was a high prevalence of the p.R337H tection include surveillance and risk-reducing surgeries. In (12.1%). These results suggest that inheritance of individuals without a previously identified pathogenic var- p.R337H may contribute to a significant number of BC iant, the absence of a pathogenic variant cannot de- cases in Brazil. finitively exclude hereditary cancer, because some Currently, in Brazil, genetic testing for TP53 mutation is for individuals may still harbor an elevated risk of HBOC families who fulfill certain criteria, which may include all caused by unknown/unidentified genetic risk factors. In cases of BC below age 35 years, regardless of family this scenario, models estimating cancer risk on the basis 27,39 history. Recent studies suggested that all women with of family history and individual risk factors should be premenopausal BC in Brazil should be tested for communicated to the patient. It is important to investigate 40,41 p.R337H. Effective screening strategies for LFS rep- both maternal and paternal lineages to prevent missing resent a major challenge because of the wide spectrum of additional cancer risk. tumors and the variable ages of onset. Given the sus- Whenever a variant of uncertain significance (VUS) is pected high population prevalence of the founder mu- identified, this result must be considered inconclusive and tation in Brazil, and the public health issue it may no clinical action is justified. The Brazilian population is constitute, a better knowledge of its country-wide prev- highly admixed, and there is likely an increased prevalence alence, as well as the effective management of cost- of VUS. Nevertheless, preliminary data have shown effective strategies dedicated to the Brazilian population, a prevalence similar to those of North American and are urgently required. European populations. The majority (. 90%) of VUS will DIAGNOSIS, MANAGEMENT, COST EFFECTIVENESS, AND 46 be reclassified to benign or likely benign categories. TREATMENT OPTIONS IN HBOC IN BRAZIL Nevertheless, VUS should always be reported and peri- Genetic cancer risk assessment (GCRA) is an interdisci- odically reassessed. Reaching back to patients regarding plinary medical practice that identifies, counsels, and new, updated testing options or techniques should also be 42,46-49 manages individuals and families at high risk of an inherited ensured. cancer syndrome. In Brazil, access to GCRA and con- MANAGEMENT OPTIONS sequent management options according to established risk Because of a lack of local studies, all recommendations for are limited. Improving access is essential to increase health Brazil are based on international data. Although surveil- and improve cancer outcomes. lance strategies for moderate-penetrance genes have Although genetic testing is not available in the Brazilian limited data, some screening strategies must be encour- public health care system, in the private system, coverage is aged (Table 3). available for molecular testing in individuals who fulfill criteria established by the Agencia Nacional de Saude. Intensive Surveillance for BRCA1 and BRCA2 Carriers Agencia Nacional de Saude guidelines include risk- An annual breast MRI in conjunction with annual mam- reducing interventions for carriers of a pathogenic germ- mography screening in BRCA1 and BRCA2 carriers from line variant (eg, risk-reducing surgeries, breast reconstruction, the age of 30 years is more sensitive than annual mam- and access to follow-up breast magnetic resonance imaging 50-54 mography alone, detecting BC at an earlier stage. MRI [MRI] in patients who decline surgery). Meeting the need for screening every 6 months has shown optimal performance adequate post-test counseling is a challenge. Regulatory 55 for women at risk of BRCA1-associated BC. Although in actions and policy recommendations are urgently needed to Brazil these resources are not sufficiently well distributed, address these issues. Table 2 lists the recommendations of breast MRI is fully covered for patients who carry a BRCA this panel in defining criteria for genetic testing for individuals pathogenic variant. Additional studies to determine the with HBOC in Brazil. combination of screening modalities, potential harms of Women diagnosed with BC or OC may be offered TFGT, exposure to mammography radiation, cost effectiveness, 56,57 with targeted therapies for BRCA carriers. As the de- and survival are needed. Future perspectives in this mand for TFGT increases, alternative models of providing field include the adoption of abbreviated MRI protocols and 442 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil TABLE 2. Recommendations for Testing Individuals With Hereditary Breast and Ovarian Cancer Individual without a cancer diagnosis should only be considered when an appropriate affected family member is unavailable for testing Individual from a family with a known BRCA1/2 pathogenic/likely pathogenic variant in a cancer predisposition gene Personal history of breast cancer and one of the following: Diagnosed at ≤ 45 years of age Diagnosed at 46-50 years of age with An additional breast cancer primary at any age ≥ 1 close blood relative with breast cancer at any age ≥ 1 close blood relative with high-grade (Gleason score ≥ 7) prostate cancer at any age An unknown or limited family history Diagnosed at ≤ 60 years of age with triple-negative breast cancer Diagnosed at any age with ≥ 1 close blood relative with Breast cancer diagnosed at ≤ 50 years of age; or Ovarian carcinoma, or Male breast cancer, or Metastatic prostate cancer, or Pancreatic cancer ≥ 2 additional diagnoses of breast cancer at any age in patient and/or in close blood relatives Personal history of male breast cancer Ashkenazi Jewish ancestry Personal history of ovarian carcinoma Personal history of pancreatic cancer Personal history of metastatic prostate cancer Personal history of high-grade prostate cancer (Gleason score ≥ 7) at any age with ≥ 1 close blood relative with ovarian carcinoma, pancreatic cancer, or metastatic prostate cancer at any age, or breast cancer at , 50 years of age ≥ 2 close blood relatives with breast or prostate cancer (any grade) at any age, or Ashkenazi Jewish ancestry BRCA1/2 pathogenic/likely pathogenic variant detected by tumor profiling on any tumor type in the absence of germline pathogenic/likely pathogenic variant analysis Regardless of family history, some individuals with a BRCA-related cancer may benefit from genetic testing to determine eligibility for targeted treatment An individual who does not meet the other criteria but with ≥ 1 first- or second-degree blood relative meeting any of the previously mentioned criteria; the significant limitations of interpreting test results for an unaffected individual should be discussed 58,59 the use of less contrast to reduce costs. OC screening is Contralateral Risk-Reducing Mastectomy for BRCA1 and not recommended. However, in patients who decline risk- BRCA2 Carriers reducing salpingo-oophorectomy, transvaginal ultrasound Cumulative contralateral BC risk 20 years after a first pri- and serum CA-125 may be considered, at the clinician’s mary BC is 40% for BRCA1 and 26% for BRCA2 carriers. discretion. Current evidence suggests that contralateral risk-reducing mastectomy is effective for BRCA1 carriers, reducing Risk-Reducing Bilateral Mastectomy for BRCA1 and 64-67 mortality. BRCA2 Carriers Bilateral mastectomy is associated with . 90% risk re- Risk-Reducing Bilateral Salpingo-Oophorectomy for duction in BC. In BRCA1 and BRCA2 carriers, nipple- BRCA1 and BRCA2 Carriers sparing mastectomy is associated with a low rate of 61,62 Bilateral salpingo-oophorectomy (BSO) confers a 72%- complications. Surveillance strategies after risk- 88% risk reduction in OC and fallopian tubal cancer. It is reducing mastectomy are not well established and associated with a reduction in OC-specific and all-cause should be addressed on a case-by-case basis. A recent 60,68 mortality in BRCA carriers. Therefore, BSO is recom- study showed that bilateral risk-reducing mastectomy in mended for BRCA carriers who have completed child- mutation carriers had an impact on mortality in BRCA1 bearing, and it should be performed by age 35-40 years in carriers, although the impact in BRCA2 carriers was less evident. BRCA1 carriers, by age 40-45 years in BRCA2 carriers, or JCO Global Oncology 443 Achatz et al 444 © 2020 by American Society of Clinical Oncology TABLE 3. Cancer Risk and Management in Non-BRCA Hereditary Breast and Ovarian Cancer–Related Genes Gene Breast Cancer Risk Breast Cancer Management Ovarian Cancer Risk Ovarian Cancer Management Other Cancer Risks ATM Increased risk Annual mammogram with consideration of Potentially Insufficient evidence for recommending Insufficient evidence for pancreas or tomosynthesis, and consider breast MRI with increased risk RRSO prostate cancer contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history BARD1 Potentially Insufficient evidence, manage on the basis of Unknown Insufficient evidence for management Unknown increased risk family history recommendations BRIP1 Unknown Insufficient evidence, manage on the basis of Increased risk Consider RRSO at age 45-50 years N/A family history CDH1 Increased risk Annual mammogram with consideration of No increased risk N/A Diffuse gastric cancer tomosynthesis, and consider breast MRI with contrast starting at age 30 years RRM: evidence insufficient, manage on the basis of family history CHEK2 Increased risk Annual mammogram with consideration of No increased risk N/A Colon cancer tomosynthesis, and consider breast MRI with contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history MLH1, MSH2 Unknown Insufficient evidence, manage on the basis of Increased risk Consider RRSO on completion of Colon, endometrial, and other cancers family history childbearing NBN Increased risk Annual mammogram with consideration of Unknown N/A Unknown tomosynthesis, and consider breast MRI with contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history NF1 Increased risk Annual mammogram with consideration of No increased risk N/A GIST, malignant peripheral nerve sheath tomosynthesis starting at age 30 years, and tumors, others consider breast MRI with contrast from ages 30-50 years RRM: evidence insufficient, manage on the basis of family history PALB2 Increased risk Annual mammogram with consideration of Unknown N/A Unknown tomosynthesis starting at age 30 years, and consider breast MRI at age 30 years RRM: evidence insufficient, manage on the basis of family history (Continued on following page) Recommendations for Hereditary Breast and Ovarian Cancer in Brazil JCO Global Oncology 445 TABLE 3. Cancer Risk and Management in Non-BRCA Hereditary Breast and Ovarian Cancer–Related Genes (Continued) Gene Breast Cancer Risk Breast Cancer Management Ovarian Cancer Risk Ovarian Cancer Management Other Cancer Risks PTEN Increased risk Annual mammogram with consideration of No increased risk N/A Thyroid, endometrial, renal, and colon tomosynthesis starting at age 30 years, and cancer consider breast MRI at age 30 years RRM: evidence insufficient, manage on the basis of family history RAD51C, Unknown Insufficient evidence, manage on the basis of Increased risk Consider RRSO at age 45-50 years Unknown RAD51D family history STK11 Increased risk Annual mammogram with consideration of Increased risk Insufficient evidence for management GI tumors tomosynthesis, and consider breast MRI with recommendations contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history TP53 Increased risk Annual mammogram with consideration of No increased risk N/A Sarcomas, adrenocortical carcinoma, brain tomosynthesis, and consider breast MRI with tumors, and others contrast starting at age 25 years RRM: discuss option of risk-reducing mastectomy NOTE. Adapted from National Comprehensive Cancer Network. Abbreviations: GIST, gastrointestinal stromal tumor; MRI, magnet resonance imaging; N/A, not available; RRM, risk-reducing mastectomy; RRSO, risk-reducing salpingo-oophorectomy. Predisposes to lobular breast cancer. Mucinous ovarian cancer. Achatz et al 446 © 2020 by American Society of Clinical Oncology TABLE 4. Recommendations for Overcoming Barriers to Adequate Diagnosis and Management of Hereditary Breast and Ovarian Cancer in Brazil Access Barriers Education Barriers Quality Assurance Barriers Lack of a structured referral network in both public and private Limited public awareness of genetic risk and of the benefits of Lack of regulatory guidelines governing quality control of health care systems GCRA laboratories and genetic tests Insufficient number of trained professionals who are able to Incomplete/incorrect counseling provided by professionals with Lack of continued assessment of the quality of the clinical services recognize and provide genetic counseling to patients with limited knowledge in the field provided in cancer genetics a higher cancer risk Absence of genetic testing in the public system and limited access Limited knowledge of HBOC syndrome and tests among health Lack of adequate research budget for epidemiologic studies to for coverage in the private setting care professionals at all levels of care delineate hereditary cancer in the country Limited availability to genetic counseling in both public and Reluctance of at-risk patients and family members to seek genetic Lack of funding to develop innovative solutions to overcome local private systems testing and counseling barriers High cost of genetic tests Cultural and religious barriers Lack of inclusion of GCRA and surveillance of patients in the Patient and family fears and misconceptions national cancer policy Abbreviations: GCRA, genetic cancer risk assessment; HBOC, hereditary breast and ovarian cancer. Patients must fulfill Agencia Nacional de Saude criteria, including the need for a prescription from a board-certified clinical geneticist to qualify for reimbursement. Recommendations for Hereditary Breast and Ovarian Cancer in Brazil individualized, on the basis of the age of onset of OC in the MANAGEMENT OPTIONS FOR TP53 GERMLINE PATHOGENIC family. Detailed sectioning and microscopic examination of VARIANT CARRIERS ovaries and fallopian tubes from BSO in high-risk pop- All carriers of a TP53 pathogenic variant should receive ulations led to the identification of occult carcinomas in up intensive surveillance. In Brazil, because of the founder to 1.9%-9.1% of cases. After risk-reducing surgery, there variant present in a significant part of the population, is a 10% risk of recurrence after detection of an occult management is a public health situation that remains carcinoma and a 1% risk of developing a primary peritoneal unresolved. Nevertheless, breast MRI should be offered tumor. annually from age 20 years and mammography annually Early surgical castration causes early menopause and in- after age 30 years. Risk-reducing bilateral mastectomy creases the risk of cardiovascular disease and osteoporosis. and contralateral risk-reducing mastectomy should be On the basis of available data from observational studies, suggested. Whole-body MRI and brain MRI should be hormone replacement therapy after BSO should not be performed yearly from birth in carriers because of the high performed in patients affected by BC, but it has not shown risk of sarcomas and CNS, adrenocortical, and other an increased risk of BC among cancer-free BRCA carriers tumors. who have undergone risk-reduction bilateral mastectomy. COST-EFFECTIVENESS OF GENETIC TESTING Chemoprevention for BRCA1 and BRCA2 Carriers BRCA testing is cost effective in BC and OC. It is associated Large primary prevention trials with tamoxifen, 20 mg once with reduced risk and improved survival in female carriers, per day for 5 years, have demonstrated that BC risk can be with benefits when testing is extended to family members reduced by 40%-50% in women at high risk, although not 79,80 (cascade testing). Presymptomatic cancer surveillance necessarily in pathogenic variant carriers. Limited data is cost effective for patients with germline pathogenic are available regarding the benefit of tamoxifen in BRCA variants in TP53. carriers, but it may be considered for patients who do not 72,73 want to undergo risk-reducing surgery. There are no Risk-reduction surgery and intensive breast screening data on the benefit of raloxifene or aromatase inhibitors in were cost effective in models of BRCA carrier risk BRCA carriers. management. In Brazil, BRCA1/BRCA2 diagnostic and management strategies for patients with OC were consid- PolyADP-Ribose Polymerases in BRCA-Associated OC for ered cost effective but only when cancer-unaffected rel- BRCA1 and BRCA2 Carriers atives of OC mutation carriers were included in the PolyADP-ribose polymerases (PARP) inhibitor is a targeted model. therapy that acts on a deficiency in the HR pathway. In OC, 2 randomized phase III trials (SOLO-2 and NOVA) CURRENT BARRIERS AND RECOMMENDATIONS FOR demonstrated improved progression-free survival with OVERCOMING BARRIERS TO ADEQUATE DIAGNOSIS AND monotherapy PARP inhibitor as maintenance therapy MANAGEMENT OF HBOC IN BRAZIL in patients with recurrent, platinum-sensitive BRCA- Despite evidence of the benefits of genetic counseling, 74,75 associated OC and HR-deficient tumors. In first-line testing, and adequate risk management, access is limited treatment, SOLO-1 showed better progression-free survival in Brazil and in most Latin American countries (Table 4). To with PARP inhibitor (olaparib) maintenance treatment after address these limitations, strategies related to public usual chemotherapy in BRCA-associated stage III-IV high- awareness, education, integrated services, implementa- grade serous or endometrial OC. Agencia Nacional de tion, and monitoring are needed. Government, medical ˆ ´ Vigilancia Sanitaria has approved olaparib for relapsed societies, patient organizations, academic centers, and the high-grade OC and for first-line BRCA-associated serous private sector should create a multistakeholder commission and endometrioid high-grade OC, but it is not yet available to develop and promote the incorporation of GCRA and to the public or in the private health system. management into the public and private health care sys- PARP Inhibitor in BRCA-Associated BC for BRCA1 and tems. Such a plan should include the following: BRCA2 Carriers 1. Establishment of genetic health benefits, including Two phase III trials (OlympiAD and EMBRACA) randomly genetic testing, counseling, and long-term manage- assigned patients after chemotherapy in HER2-negative, ment, accessible to patients in both public and private BRCA-associated metastatic BC and showed longer health care systems: progression-free survival with PARP inhibitor. The Food � The Brazilian National Cancer Control Policy should and Drug Administration has approved 2 PARP inhibi- be updated to include essential genetic health 77 78 tors (olaparib and talazoparib ) for germline BRCA- benefits. associated metastatic BC. In Brazil, olaparib was ap- � Regulatory agencies in the Brazilian Ministry of ˆ ˆ proved in this setting by Agencia Nacional de Vigilancia Health should prioritize the incorporation of policies Sanitaria in 2018. related to hereditary cancer. JCO Global Oncology 447 Achatz et al � Guidelines that ensure coverage for genetic services 6. A Brazilian network of reference centers should be in private health care should be updated on an expanded and the insertion of GCRA and genetic annual basis and should include genetic testing testing should be championed in both public and coverage for cancer-unaffected individuals when private health care systems. first- and second-degree relatives fulfill criteria. 7. Continuing professional education and periodic 2. Development of a 3-tiered training program for health recertification should be implemented to guarantee professionals. clinical and laboratory services. Professional societies � Tier 1: Basic genetics education and continued should oversee these efforts. medical education should be provided to all health 8. Government, medical societies, health care pro- care professionals to enable recognition and referral fessionals, and patient organizations should support of at-risk patients; education programs to promote public awareness of � Tier 2: A minimum curriculum on hereditary cancer the importance of understanding personal and family should be included in training programs in spe- genetic risk factors and their influence on cancer cialties related to cancer care, and continuing management. medical education should be required; 9. Politicians should be encouraged to pass laws pro- � Tier 3: Specialty training programs should be de- tecting individuals against genetic discrimination by veloped and expanded for health care professionals employers and insurance companies. seeking to conduct GCRA. 10. Systematic reporting should be encouraged. Results 3. In TFGT, a streamlined approach should be imple- from clinical and research-focused genetic testing mented. Traditional GCRA should be available when- should be made available in public databases on ever indicated. Research studies should be conducted human genomic variations. to validate whether a streamlined approach is effective There is a great need to expand hereditary cancer testing in Brazil. and counseling in Brazil. Understanding Brazil’s unique 4. Genetic counseling and risk assessment should be social and structural barriers and mounting a strong, timely offered in a multidisciplinary setting involving multiple response to this public health problem is crucial. Increased health care professionals to ensure the most appro- knowledge and awareness of HBOC among nongenetic priate management of patients and their families. health care professionals, as well as the general population, 5. Public health officials should be educated on the public health officials, and patient organizations, would importance of GCRA, guaranteeing access to genetic health benefits as part of the strategic national cancer advance translational efforts to improve cancer care and control plan. outcomes. AFFILIATIONS SUPPORT ´ ˆ Centro de Oncologia, Hospital Sırio-Libanes, São Paulo, Brazil Supported by a grant from the Americas Health Foundation, a 501(c)(3) Nucleo Mama Porto Alegre and Associação Hospitalar Moinhos de nonprofit organization dedicated to improving health care throughout the Vento, Porto Alegre, Brazil Latin American Region, and by an unrestricted grant from AstraZeneca. Oncologia D’or, Rede D’or São Luiz, Brazil Centro de Investigação Translacional em Oncologia, Instituto do Cancer AUTHOR CONTRIBUTIONS do Estado de Sao Paulo, Hospital das Clınicas da Faculdade de Medicina Conception and design: All authors da Universidade de Sao Paulo, São Paulo, Brazil Provision of study material or patients: Maira Caleffi Programa da Saude da Mulher, Hospital Israelita Albert Einstein, São Collection and assembly of data: Rodrigo Guindalini, Paulo, Brazil Patricia Ashton-Prolla Centro de Oncologia e Hematologia, Hospital Israelita Albert Einstein, Data analysis and interpretation: Rodrigo Guindalini, São Paulo, Brazil Patricia Ashton-Prolla Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Manuscript writing: All authors Grupo Brasileiro de Oncologia Ginecologica, ´ Belo Horizonte, Brazil Final approval of manuscript: All authors DOM Oncologia, Minas Gerais, Brazil Accountable for all aspects of the work: All authors Departmento de Genetica, ´ Universidade Federal do Rio Grande do Sul Laboratorio ´ de Medicina Genomic ˆ a, Hospital de Cl´ınicas de Porto AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF Alegre, Porto Alegre, Brazil INTEREST The Americas Health Foundation had no role in deciding the content of The following represents disclosure information provided by authors of this article, and the recommendations are those solely of the panel this manuscript. All relationships are considered compensated unless members. otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the CORRESPONDING AUTHOR subject matter of this manuscript. For more information about ASCO’s Maria Isabel Achatz, MD, PhD, Rua Dona Adma Jafet 115, São Paulo, SP conflict of interest policy, please refer to www.asco.org/rwc or ascopubs. Brazil, 01308-060; Twitter: @AchatzIsabel; e-mail: miachatz@ org/go/site/misc/authors.html. gmail.com. 448 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil Open Payments is a public database containing information reported by Speakers’ Bureau: AstraZeneca, Roche, MSD, Bayer, Merck, Teva, companies about payments made to US-licensed physicians (Open Boehringer Ingelheim, Bristol-Myers Squibb Payments). Travel, Accommodations, Expenses: AstraZeneca, Roche Maria Isabel Achatz Angelica Nogueira-Rodrigues Speakers’ Bureau: AstraZeneca, MSD Oncology Honoraria: Roche, MSD, AstraZeneca Consulting or Advisory Role: Roche, AstraZeneca, MSD, Eisai Rodrigo Guindalini Patricia Ashton-Prolla Employment: CLION, Grupo CAM, Oncologia D’or Stock and Other Ownership Interests: Mendelics Analise ´ Genomica ˆ Research Funding: AstraZeneca Brazil (Inst) Consulting or Advisory Role: AstraZeneca Brazil, Merck Brazil No other potential conflicts of interest were reported. REFERENCES 1. Szabo CI, King MC: Inherited breast and ovarian cancer. Hum Mol Genet 4:1811-1817, 1995 2. Roy R, Chun J, Powell SN: BRCA1 and BRCA2: Different roles in a common pathway of genome protection. Nat Rev Cancer 12:68-78, 2011 3. Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003 4. Mersch J, Jackson MA, Park M, et al: Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121:269-275, 2015 5. Kuchenbaecker KB, Hopper JL, Barnes DR, et al: Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402-2416, 2017 6. Risch HA, McLaughlin JR, Cole DE, et al: Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: A kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98:1694-1706, 2006 7. Kalia SS, Adelman K, Bale SJ, et al: Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): A policy statement of the American College of Medical Genetics and Genomics. Genet Med 19:249-255, 2017 [Erratum: Genet Med, 2017] 8. Peters ML, Garber JE, Tung N: Managing hereditary breast cancer risk in women with and without ovarian cancer. Gynecol Oncol 146:205-214, 2017 9. Graffeo R, Livraghi L, Pagani O, et al: Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat 160:393-410, 2016 10. Buys SS, Sandbach JF, Gammon A, et al: A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 123:1721-1730, 2017 11. Eliade M, Skrzypski J, Baurand A, et al: The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? Oncotarget 8:1957-1971, 2017 12. Robson M, Domchek S: Broad application of multigene panel testing for breast cancer susceptibility-Pandora’s box is opening wider. JAMA [epub ahead of print on October 3, 2019] 13. Meiser B, Quinn VF, Gleeson M, et al: When knowledge of a heritable gene mutation comes out of the blue: Treatment-focused genetic testing in women newly diagnosed with breast cancer. Eur J Hum Genet 24:1517-1523, 2016 14. Rebbeck TR, Mitra N, Wan F, et al: Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313:1347-1361, 2015 ´ ´ 15. Baquero JM, Benıtez-Buelga C, Fernandez V, et al: A common SNP in the UNG gene decreases ovarian cancer risk in BRCA2 mutation carriers. Mol Oncol 13:1110-1120, 2019 16. Rebbeck TR, Friebel TM, Friedman E, et al: Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593-620, 2018 17. Carraro DM, Koike Folgueira MA, Garcia Lisboa BC, et al: Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: A portrait of early-onset breast cancer in Brazil. PLoS One 8:e57581, 2013 18. Silva FC, Lisboa BC, Figueiredo MC, et al: Hereditary breast and ovarian cancer: Assessment of point mutations and copy number variations in Brazilian patients. BMC Med Genet 15:55, 2014 19. Fernandes GC, Michelli RA, Galvão HC, et al: Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget 7:80465-80481, 2016 20. Maistro S, Teixeira N, Encinas G, et al: Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer 16:934, 2016 21. Alemar B, Herzog J, Brinckmann Oliveira Netto C, et al: Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet 209:417-422, 2016 22. Alemar B, Gregorio ´ C, Herzog J, et al: BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? PLoS One 12:e0187630, 2017 [Erratum: PLoS One, 2018] 23. Palmero EI, Carraro DM, Alemar B, et al: The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep 8:9188, 2018 24. de Souza Timoteo AR, Gonçalves AEMM, Sales LAP, et al: A portrait of germline mutation in Brazilian at-risk for hereditary breast cancer. Breast Cancer Res Treat 172:637-646, 2018 25. Felix GE, Abe-Sandes C, Machado-Lopes TM, et al: Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: Characterizing a Northeast Brazilian Population. Hum Genome Var 1:14012, 2014 26. National Comprehensive Cancer Network: NCCN guidelines. https://www.nccn.org/professionals/physician_gls/default.aspx 27. Agencia Nacional de Saude: Resolução Normativa – RN N° 428 de 7 de Novembro deo 2017. http://www.ans.gov.br/component/legislacao/?view=legislacao& task=PDFAtualizado&format=raw&id=MzUwMg== 28. Salzano FM, Bortolini MC: The Evolution and Genetics of Latin American Populations. Cambridge, UK, Cambridge University Press, 2002 29. Pena SD, Di Pietro G, Fuchshuber-Moraes M, et al: The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One 6:e17063, 2011 30. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al: A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358-5362, 1988 31. Børresen-Dale AL: TP53 and breast cancer. Hum Mutat 21:292-300, 2003 JCO Global Oncology 449 Achatz et al 32. Olivier M, Langerød A, Carrieri P, et al: The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157-1167, 33. Silwal-Pandit L, Vollan HK, Chin SF, et al: TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 20:3569-3580, 2014 34. Mai PL, Khincha PP, Loud JT, et al: Prevalence of cancer at baseline screening in the National Cancer Institute Li-Fraumeni syndrome cohort. JAMA Oncol 3:1640-1645, 2017 35. Masciari S, Dillon DA, Rath M, et al: Breast cancer phenotype in women with TP53 germline mutations: A Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat 133:1125-1130, 2012 36. Mastellaro MJ, Seidinger AL, Kang G, et al: Contribution of the TP53 R337H mutation to the cancer burden in southern Brazil: Insights from the study of 55 families of children with adrenocortical tumors. Cancer 123:3150-3158, 2017 37. Achatz MI, Zambetti GP: The inherited p53 mutation in the Brazilian population. Cold Spring Harb Perspect Med 6:a026195, 2016 38. Giacomazzi J, Graudenz MS, Osorio CA, et al: Prevalence of the TP53 p.R337H mutation in breast cancer patients in Brazil. PLoS One 9:e99893, 2014 39. Chompret A, Abel A, Stoppa-Lyonnet D, et al: Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38:43-47, 2001 40. Andrade KC, Santiago KM, Fortes FP, et al: Early-onset breast cancer patients in the south and southeast of Brazil should be tested for the TP53 p.R337H mutation. Genet Mol Biol 39:199-202, 2016 41. Hahn EC, Bittar CM, Vianna FSL, et al: TP53 p.Arg337His germline mutation prevalence in southern Brazil: Further evidence for mutation testing in young breast cancer patients. PLoS One 13:e0209934, 2018 42. Weitzel JN, Blazer KR, MacDonald DJ, et al: Genetics, genomics and cancer risk assessment: State of the art and future directions in the era of personalized medicine. CA Cancer J Clin 61:327-359, 2011 43. Quinn VF, Meiser B, Kirk J, et al: Streamlined genetic education is effective in preparing women newly diagnosed with breast cancer for decision making about treatment-focused genetic testing: A randomized controlled noninferiority trial. Genet Med 19:448-456, 2017 44. Colombo N, Huang G, Scambia G, et al: Evaluation of a streamlined oncologist-led BRCA mutation testing and counseling model for patients with ovarian cancer. J Clin Oncol 36:1300-1307, 2018 45. Copson ER, Maishman TC, Tapper WJ, et al: Germline BRCA mutation and outcome in young-onset breast cancer (POSH): A prospective cohort study. Lancet Oncol 19:169-180, 2018 46. Slavin TP, Manjarrez S, Pritchard CC, et al: The effects of genomic germline variant reclassification on clinical cancer care. Oncotarget 10:417-423, 2019 47. Easton DF, Pharoah PD, Antoniou AC, et al: Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372:2243-2257, 2015 48. Crawford B, Adams SB, Sittler T, et al: Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients. Breast Cancer Res Treat 163:383-390, 2017 49. Mersch J, Brown N, Pirzadeh-Miller S, et al: Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA 320:1266-1274, 2018 50. Kuhl C, Weigel S, Schrading S, et al: Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: The EVA trial. J Clin Oncol 28:1450-1457, 2010 51. Le-Petross HT, Whitman GJ, Atchley DP, et al: Effectiveness of alternating mammography and magnetic resonance imaging for screening women with deleterious BRCA mutations at high risk of breast cancer. Cancer 117:3900-3907, 2011 52. Riedl CC, Luft N, Bernhart C, et al: Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density. J Clin Oncol 33:1128-1135, 2015 53. Phi XA, Saadatmand S, De Bock GH, et al: Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: Individual patient data meta-analysis. Br J Cancer 114:631-637, 2016 54. Saslow D, Boetes C, Burke W, et al: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57:75-89, 2007 55. Guindalini RSC, Zheng Y, Abe H, et al: Intensive surveillance with biannual dynamic contrast-enhanced magnetic resonance imaging downstages breast cancer in BRCA1 mutation carriers. Clin Cancer Res 25:1786-1794, 2019 56. Pijpe A, Andrieu N, Easton DF, et al: Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: Retrospective cohort study (GENE-RAD-RISK). BMJ 345:e5660, 2012 57. Plevritis SK, Kurian AW, Sigal BM, et al: Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA 295:2374-2384, 2006 58. Pataky R, Armstrong L, Chia S, et al: Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers. BMC Cancer 13:339, 2013 59. Kuhl CK, Schrading S, Strobel K, et al: Abbreviated breast magnetic resonance imaging (MRI): First postcontrast subtracted images and maximum-intensity projection-a novel approach to breast cancer screening with MRI. J Clin Oncol 32:2304-2310, 2014 60. Ludwig KK, Neuner J, Butler A, et al: Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review. Am J Surg 212:660-669, 2016 61. Yao K, Liederbach E, Tang R, et al: Nipple-sparing mastectomy in BRCA1/2 mutation carriers: An interim analysis and review of the literature. Ann Surg Oncol 22:370-376, 2015 [Erratum: Ann Surg Oncol 21:S788, 2014] 62. Jakub JW, Peled AW, Gray RJ, et al: Oncologic safety of prophylactic nipple-sparing mastectomy in a population with BRCA mutations: A multi-institutional study. JAMA Surg 153:123-129, 2018 63. Heemskerk-Gerritsen BAM, Jager A, Koppert LB, et al: Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 177:723-733, 2019 64. Boughey JC, Hoskin TL, Degnim AC, et al: Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer. Ann Surg Oncol 17:2702-2709, 2010 65. Lostumbo L, Carbine NE, Wallace J: Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 11:CD002748, 2010 66. Metcalfe K, Gershman S, Ghadirian P, et al: Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: Ret- rospective analysis. BMJ 348:g226, 2014 67. Evans DG, Ingham SL, Baildam A, et al: Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer. Breast Cancer Res Treat 140:135-142, 2013 68. George SH, Shaw P: BRCA and early events in the development of serous ovarian cancer. Front Oncol 4:5, 2014 69. Powell CB, Chen LM, McLennan J, et al: Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: Experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol. Int J Gynecol Cancer 21:846-851, 2011 450 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil 70. Kotsopoulos J, Gronwald J, Karlan BY, et al: Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA Oncol 4:1059-1065, 2018 71. Cuzick J, Sestak I, Bonanni B, et al: Selective oestrogen receptor modulators in prevention of breast cancer: An updated meta-analysis of individual participant data. Lancet 381:1827-1834, 2013 72. King MC, Wieand S, Hale K, et al: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286:2251-2256, 2001 73. Phillips KA, Milne RL, Rookus MA, et al: Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol 31:3091-3099, 74. Pujade-Lauraine E, Ledermann JA, Selle F, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18:1274-1284, 2017 75. Mirza MR, Monk BJ, Herrstedt J, et al: Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375:2154-2164, 2016 76. Moore K, Colombo N, Scambia G, et al: Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379:2495-2505, 2018 77. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017 [Erratum: N Engl J Med, 2017] 78. Litton JK, Rugo HS, Ettl J, et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753-763, 2018 79. Tuffaha HW, Mitchell A, Ward RL, et al: Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers. Genet Med 20:985-994, 2018 80. Eccleston A, Bentley A, Dyer M, et al: A cost-effectiveness evaluation of germline BRCA1 and BRCA2 testing in UK women with ovarian cancer. Value Health 20:567-576, 2017 81. Tak CR, Biltaji E, Kohlmann W, et al: Cost-effectiveness of early cancer surveillance for patients with Li-Fraumeni syndrome. Pediatr Blood Cancer 66:e27629, 82. Muller ¨ D, Danner M, Schmutzler R, et al: Economic modeling of risk-adapted screen-and-treat strategies in women at high risk for breast or ovarian cancer. Eur J Health Econ 20:739-750, 2019 83. Ramos MCA, Folgueira MAAK, Maistro S, et al: Cost effectiveness of the cancer prevention program for carriers of the BRCA1/2 mutation. Rev Saude Publica 52:94, 2018 84. Mitropoulos K, Al Jaibeji H, Forero DA, et al: Success stories in genomic medicine from resource-limited countries. Hum Genomics 9:11, 2015 85. Laraqui A, Uhrhammer N, Rhaffouli HE, et al: BRCA genetic screening in Middle Eastern and North African: Mutational spectrum and founder BRCA1 mutation (c.798_799delTT) in North African. Dis Markers 2015:194293, 2015 86. Seymour HJ, Wainstein T, Macaulay S, et al: Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient? S Afr Med J 106:264-267, 2016 ´ ´ 87. Villarreal-Garza C, Alvarez-Gomez RM, Perez-Plasencia C, et al: Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico. Cancer 121:372-378, 2015 88. Cavallone L, Arcand SL, Maugard CM, et al: Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer 9:507-517, 2010 89. Manchanda R, Loggenberg K, Sanderson S, et al: Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: A randomized controlled trial. J Natl Cancer Inst 107:379, 2014 90. Peixoto A, Santos C, Pinheiro M, et al: International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation. Breast Cancer Res Treat 127:671-679, 2011 91. Rafnar T, Benediktsdottir KR, Eldon BJ, et al: BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: A population-based study. Eur J Cancer 40:2788-2793, 2004 92. Van Der Looij M, Szabo C, Besznyak I, et al: Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary. Int J Cancer 86:737-740, 2000 nn n JCO Global Oncology 451 Achatz et al APPENDIX TABLE A1. Breast Cancer Risk and Protective Factors Nongenetic Exposures Variable Hereditary Ovarian Cancer Risk Factor b c Late age at menarche BRCA1: Null results or borderline protective effect b,d BRCA2: null results Alcohol consumption Three studies reported on alcohol use, all of which reported null results Smoking BRCA1: One article studied coffee intake and smoking with null results in each category f,g BRCA2: A pooled estimate of 2 studies showed an increased risk for more than 4 years of smoking v never, whereas an ever v never meta-analysis of smoking produced null results Coffee/caffeine intake BRCA1: One article studied coffee intake and smoking, with null results in each category Oral contraceptive use BRCA1: Studies reported a decreased risk of ovarian cancer for BRCA1 mutation carriers with ever v never use; when the oral contraceptive use occurred for . 1 year, there was a statistically significant b,c,h,i decreased risk, ranging from a 33% to a 80% reduction BRCA2: Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA2 mutations (0.39 h-j [0.23-0.66]; P = .0004) b,k,l Age at first live birth BRCA1/2: The meta-analysis results were largely null Parity BRCA1/2: Studies reported on trend per birth, and a meta-analysis showed statistically significant risk b,c,i,l reduction only seen in women with . 4 live births Breastfeeding BRCA1: A study reported a statistically significant reduction in ovarian cancer risk with ever v never breastfeeding. b,j BRCA2: Two studies reported no association for ever v never, ≤ 1 year v never, and . 1 year v never i,m Combined HRT exposure BRCA1: Hormone replacement therapy was examined, with null effects reported Tamoxifen (contralateral breast cancer) BRCA1: One study reported a null effect of tamoxifen i,n BRCA2: Studies reported a null effect b,h,j Tubal ligation BRCA1: Studies that evaluated tubal ligation reported a reduction in risk for ever having a tubal ligation b,h,j BRCA2: No protective effect of tubal ligation was seen among carriers of the mutation NOTE. Boldface indicates significance. Abbreviation: HRT, hormone replacement therapy. Friebel TM, Domchek SM, Rebbeck TR: Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: Systematic review and meta-analysis. J Natl Cancer Inst 106:dju091, 2014. Antoniou AC, Rookus M, Andrieu N, et al: Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: Results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 18:601-610, 2009. Gronwald J, Byrski T, Huzarski T, et al: Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Res Treat 95:105-109, 2006. Park B, Hopper JL, Win AK, et al: Reproductive factors as risk modifiers of breast cancer in BRCA mutation carriers and high-risk non-carriers. Oncotarget 8:102110-102118, 2017. McGuire V, John EM, Felberg A, et al: No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages ,50 years. Cancer Epidemiol Biomarkers Prev 15:1565-1567, 2006. Breast Cancer Family Registry; Kathleen Cuningham Consortium for Research into Familial Breast Cancer (Australasia); Ontario Cancer Genetics Network (Canada): Smoking and risk of breast cancer in carriers of mutation in BRCA1 or BRCA2 aged less than 50 years. Breast Cancer Res Treat 109:67-75, 2008. Ginsburg O, Ghadirian P, Lubinski J, et al: Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: An update. Breast Cancer Res Treat 114:127-135, 2009. Narod SA, Sun P, Ghadirian P, et al: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: A case-control study. Lancet 357:1467-1470, 2001. Vicus D, Rosen B, Lubinski J, et al: Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers. Gynecol Oncol 115:135-137, 2009. McLaughlin JR, Risch HA, Lubinski J, et al: Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: A case-control study. Lancet Oncol 8:26-34, 2007. Lecarpentier J, Nogues C, Mouret-Fourme E, et al: Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO). Breast Cancer Res 14:R99, 2012. Milne RL, Osorio A, Ramon y Cajal T, et al: Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119:221-232, 2010. Kotsopoulos J, Lubinski J, Neuhausen SL, et al: Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Gynecol Oncol 100:83-88, 2006. Phillips K-A, Milne RL, Bassett JK, et al: Tamoxifen and contralateral breast cancer (CBC) risk for BRCA1 and BRCA2 mutation carriers: An updated analysis of data from the Kathleen Cuningham Foundation consortium for research into familial breast cancer, the International BRCA1 and BRCA2 carrier cohort study and the breast cancer family registry. Cancer Res 78, 2018 (abstr). 452 © 2020 by American Society of Clinical Oncology http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JCO Global Oncology Pubmed Central

Recommendations for Advancing the Diagnosis and Management of Hereditary Breast and Ovarian Cancer in Brazil

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special articles abstract Recommendations for Advancing the Diagnosis and Management of Hereditary Breast and Ovarian Cancer in Brazil 1 2 3,4 5,6 Maria Isabel Achatz, MD, PhD ; Maira Caleffi, MD, PhD ; Rodrigo Guindalini, MD, PhD ; Renato Moretti Marques, PhD ; 7,8,9 10,11 Angelica Nogueira-Rodrigues, PhD ; and Patricia Ashton-Prolla, MD, PhD PURPOSE The objective of this review was to address the barriers limiting access to genetic cancer risk as- sessment and genetic testing for individuals with suspected hereditary breast and ovarian cancer (HBOC) through a review of the diagnosis and management steps of HBOC. METHODS A selected panel of Brazilian experts in fields related to HBOC was provided with a series of relevant questions to address before the multiday conference. During this conference, each narrative was discussed and edited by the entire group, through numerous drafts and rounds of discussion, until a consensus was achieved. RESULTS The authors propose specific and realistic recommendations for improving access to early diagnosis, risk management, and cancer care of HBOC specific to Brazil. Moreover, in creating these recommendations, the authors strived to address all the barriers and impediments mentioned in this article. CONCLUSION There is a great need to expand hereditary cancer testing and counseling in Brazil, and changing current policies is essential to accomplishing this goal. Increased knowledge and awareness, together with regulatory actions to increase access to this technology, have the potential to improve patient care and pre- vention and treatment efforts for patients with cancer across the country. JCO Global Oncol 6:439-452. © 2020 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION panel to address. A written response to each question was drafted by each expert and was discussed during Approximately 10% and 25% of all breast (BC) and 1 a multiday meeting. Questions were edited by the ovarian cancers (OC), respectively, are hereditary. entire group, through numerous drafts and rounds of Identification of pathogenic germline variants in discussion, until complete consensus was obtained. high-/moderate-penetrance cancer-predisposing genes allows the implementation of strategies for cancer risk BURDEN AND EPIDEMIOLOGY OF, AND RISK FACTORS reduction and early detection. In Brazil, there is limited FOR, HBOC access to cancer risk assessment and genetic testing HBOC is a highly penetrant, autosomal dominant for individuals with suspected hereditary cancer, as disorder mostly caused by pathogenic and likely well as limited information on its burden in the country. pathogenic germline variants in BRCA1 and BRCA2 Therefore, the objective of this study was to make ASSOCIATED genes. BRCA1 and BRCA2 are tumor suppres- CONTENT harmonized recommendations for improving early sor genes that repair double-stranded DNA breaks Appendix detection, risk management, and cancer care of through homologous recombination (HR). Individuals Author affiliations patients with hereditary breast and ovarian cancer harboring germline pathogenic variants in BRCA1 and and support (HBOC). BRCA2 are predisposed to BC (lifetime risk up to information (if applicable) appear at 85% and 45%, respectively) and OC (lifetime risk up to METHODOLOGY the end of this 39% and 11%, respectively), as well as other The Americas Health Foundation convened a 6- article. 3-5 malignancies. member panel of clinical and scientific experts in Accepted on January 21, 2020 and oncology, gynecology, genetics, and applied genomics The population prevalence of BRCA1 and BRCA2 published at from Brazil. PubMed and Embase were used to pathogenic variants is 1:150-1:200 individuals in ascopubs.org/journal/ 6 conduct a literature review and to identify Brazilian North American and European populations. Mutation go on March 10, experts who have published in the field of HBOC since prevalence varies according to ethnicity, the genetic 2020: DOI https://doi. 2012. To better focus the discussion, Americas Health testing criteria used, age at cancer diagnosis, and org/10.1200/JGO.19. 00170 Foundation staff developed specific questions for the family history. The catalog of germline variants in 439 Achatz et al CONTEXT Key Objective How can the diagnosis and management of hereditary breast and ovarian cancer be improved in Brazil? A panel of Brazilian experts proposes recommendations for improving access to early diagnosis, risk management, and cancer care of hereditary breast and ovarian cancer. Knowledge Generated Understanding Brazil’s unique social and structural barriers is crucial to expanding access to genetic cancer risk assessment. Government, medical societies, patient organizations, academic centers, and the private sector should collaborate to create a multistakeholder commission to develop and promote the incorporation of genetic cancer risk assessment. Relevance Increased knowledge and awareness, together with regulatory actions to expand hereditary cancer testing and counseling in Brazil, have the potential to improve the care of patients with cancer and reduce the cancer burden across the country. BRCA genes in different populations should be expanded germline BRCA1/2 variants, such as those described by the and made available in public databases such as ClinVar Consortium of Investigators of Modifiers of BRCA1/2. and BRCA Challenge. Risk-protecting factors (eg, breast feeding in BRCA1 car- riers) and risk-enhancing factors (eg, obesity) have been BC and OC risks may be increased by pathogenic variants identified (Appendix Table A1). Studies on cancer risk in other high-penetrance (TP53, PTEN, STK11, CDH1, and modifiers in Brazilian patients with HBOC are not currently PALB2) and moderate-penetrance (CHEK2, ATM, NF1, available. Such studies are needed to verify whether these RAD51C, RAD51D, and BRIP1) genes. The American cancer risk modifiers have a role in risk management College of Medical Genetics has recognized 25 actionable strategies tailored to Brazil’s admixed population. genes for which there is enough evidence to implement an effective cancer risk-reduction strategy. Cancer risk man- MOLECULAR EPIDEMIOLOGY OF HBOC agement has been implemented in BRCA1 and BRCA2 In the mutational landscape of BRCA1 and BRCA2 variants pathogenic carriers, whereas knowledge about the appro- in. 29,000 families substantial variation in mutation type priate management of carriers with moderate-penetrance 8 and frequency by geographical region and race/ethnicity genes is still limited. was observed. Recurrent germline BRCA variants have Multigene panel testing, including actionable genes related been described in specific populations or geographic re- to BC and OC, may be considered for patients who fulfill the gions, and some are caused by founder effects (Table 1). In clinical criteria for HBOC. Testing only BRCA genes may these situations, mutation-specific screening strategies are miss approximately one-half of the pathogenic germline efficient, such as the 3 BRCA1 and BRCA2 Ashkenazi variants involved in HBOC risk, and next-generation se- 13 founder mutations identified in 2.5% of this population. quencing allows testing genes with clinical usefulness at Nine studies have performed comprehensive BRCA mu- 9,11,12 an affordable cost. Panel testing should be recom- tation testing in 2,090 individuals from high-risk cohorts in 17-25 mended only by trained physicians to ensure adequate Brazil. Mutation prevalence estimates in individuals 26,27 genetic counseling and management. There is no added with clinical criteria are 19%-22%. Approximately value of exome and whole-genome testing in HBOC fam- 5% are large gene rearrangements. Certain variants are ilies, and this should not be recommended. Treatment- specific to Brazilian regions as a result of distinctive pat- 28,29 focused genetic testing (TFGT) and genomic tumor profiling terns of immigration in the past centuries. are currently the gold standard in defining better treatment strategies for tumors such as ovarian serous carcinomas. HEREDITARY BC RELATED TO TP53 GENE This generates an urgent need to provide more effec- In Brazil, a significant percentage of BC burden is conferred tive, timely, and adequate pre- and post-test genetic by Li-Fraumeni syndrome (LFS), because of a founder counseling. mutation, TP53 p.Arg337His (p.R337H)(NC_000017.9: Several genetic and environmental factors can modulate c.1010G.A), present in 0.3% of the southern and the penetrance of germline BRCA1 and BRCA2 pathogenic southeastern populations. LFS has a wide tumor spectrum, variants. Variant location, with the identification of clusters predisposing to premenopausal BC, sarcomas, brain tu- of mutations with differential cancer risks, may be asso- mors, and adrenocortical carcinoma, among other 14 30 ciated with higher BC or OC risks. In addition, several cancers. Strong evidence supports the association genetic variants have been identified in coding and non- between the TP53 germline variant and a worse overall and 31-33 coding regions, which may modulate the penetrance of disease-free survival in BC. In classic LFS, cancer risk 440 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil JCO Global Oncology 441 TABLE 1. Recurrent Pathogenic Variants in Hereditary Breast and Ovarian Cancer Syndrome Identified in Different Countries Continent Country Gene Mutation(s) Confirmed Founder Details First Author Africa Algeria, BRCA1 c.798_799delTT No 22% of BRCA1 mutations in North African families Laraqui Morocco, and Tunisia South Africa No BRCA1 No BRCA2 c.1374delC No 77.8% of mutation carriers had one of the Seymour c.2641G.T c.7934delG 3 Afrikaner founder mutations Americas North Mexico BRCA1 Exon 9-12 del Yes 35% and 29% of the BRCA-associated ovarian Villareal-Garza and breast cancer cases, respectively Canada BRCA1 c.4327C . T c.8537_8538del c.5266dupC Yes BRCA2 Yes Cavallone South Brazil BRCA1 Yes Fernandes Asia Israel BRCA1 c.5266dup Yes Manchanda c.68_69del Yes BRCA2 c.5946del Yes Europe Portugal BRCA2 c.156_157insAlu Yes 37.9% of BRCA2 pathogenic variants in Peixoto Portuguese families Iceland BRCA2 c.771_775del Yes Rafnar Hungary BRCA2 c.9097dup Yes Van der Looij Australia/Oceania Australia BRCA1 c.3331_3334del No Also recurrent in Hispanic populations, Europe, Rebbeck USA, and the UK Australia BRCA2 c.6275_6276del No Also recurrent in the UK, Belgium, Spain, the Rebbeck Netherlands, and North America Achatz et al by age 60 years is 90% in women and 73% in men, information to patients before genetic testing should be with an overall cumulative incidence of 50% by age sought, because there is a limited number of genetic risk 34,35 40 years. The p.R337H TP53 variant confers a life- assessment providers. A streamlined approach may be an time cancer risk that differs from typical DNA-biding effective solution. It relies on substituting traditional pretest domain TP53 pathogenic variants. Carriers have a lifetime genetic counseling with providing information, the graphic/ cancer risk of 80% in females, and 47% in males. BC is visual information to the patient, or focused counseling by 43-45 the most common malignancy diagnosed in LFS. In the treating physician. p.R337H carriers, the mean age is 40 years, and in classic UNDERSTANDING GENETIC TESTING RESULTS LFS, 32 years. In a cohort of 815 women affected by BC in In the presence of germline BRCA1/BRCA2 and TP53 southern Brazil who developed the disease before age variants, current options for risk reduction and early de- 45 years, the result was a high prevalence of the p.R337H tection include surveillance and risk-reducing surgeries. In (12.1%). These results suggest that inheritance of individuals without a previously identified pathogenic var- p.R337H may contribute to a significant number of BC iant, the absence of a pathogenic variant cannot de- cases in Brazil. finitively exclude hereditary cancer, because some Currently, in Brazil, genetic testing for TP53 mutation is for individuals may still harbor an elevated risk of HBOC families who fulfill certain criteria, which may include all caused by unknown/unidentified genetic risk factors. In cases of BC below age 35 years, regardless of family this scenario, models estimating cancer risk on the basis 27,39 history. Recent studies suggested that all women with of family history and individual risk factors should be premenopausal BC in Brazil should be tested for communicated to the patient. It is important to investigate 40,41 p.R337H. Effective screening strategies for LFS rep- both maternal and paternal lineages to prevent missing resent a major challenge because of the wide spectrum of additional cancer risk. tumors and the variable ages of onset. Given the sus- Whenever a variant of uncertain significance (VUS) is pected high population prevalence of the founder mu- identified, this result must be considered inconclusive and tation in Brazil, and the public health issue it may no clinical action is justified. The Brazilian population is constitute, a better knowledge of its country-wide prev- highly admixed, and there is likely an increased prevalence alence, as well as the effective management of cost- of VUS. Nevertheless, preliminary data have shown effective strategies dedicated to the Brazilian population, a prevalence similar to those of North American and are urgently required. European populations. The majority (. 90%) of VUS will DIAGNOSIS, MANAGEMENT, COST EFFECTIVENESS, AND 46 be reclassified to benign or likely benign categories. TREATMENT OPTIONS IN HBOC IN BRAZIL Nevertheless, VUS should always be reported and peri- Genetic cancer risk assessment (GCRA) is an interdisci- odically reassessed. Reaching back to patients regarding plinary medical practice that identifies, counsels, and new, updated testing options or techniques should also be 42,46-49 manages individuals and families at high risk of an inherited ensured. cancer syndrome. In Brazil, access to GCRA and con- MANAGEMENT OPTIONS sequent management options according to established risk Because of a lack of local studies, all recommendations for are limited. Improving access is essential to increase health Brazil are based on international data. Although surveil- and improve cancer outcomes. lance strategies for moderate-penetrance genes have Although genetic testing is not available in the Brazilian limited data, some screening strategies must be encour- public health care system, in the private system, coverage is aged (Table 3). available for molecular testing in individuals who fulfill criteria established by the Agencia Nacional de Saude. Intensive Surveillance for BRCA1 and BRCA2 Carriers Agencia Nacional de Saude guidelines include risk- An annual breast MRI in conjunction with annual mam- reducing interventions for carriers of a pathogenic germ- mography screening in BRCA1 and BRCA2 carriers from line variant (eg, risk-reducing surgeries, breast reconstruction, the age of 30 years is more sensitive than annual mam- and access to follow-up breast magnetic resonance imaging 50-54 mography alone, detecting BC at an earlier stage. MRI [MRI] in patients who decline surgery). Meeting the need for screening every 6 months has shown optimal performance adequate post-test counseling is a challenge. Regulatory 55 for women at risk of BRCA1-associated BC. Although in actions and policy recommendations are urgently needed to Brazil these resources are not sufficiently well distributed, address these issues. Table 2 lists the recommendations of breast MRI is fully covered for patients who carry a BRCA this panel in defining criteria for genetic testing for individuals pathogenic variant. Additional studies to determine the with HBOC in Brazil. combination of screening modalities, potential harms of Women diagnosed with BC or OC may be offered TFGT, exposure to mammography radiation, cost effectiveness, 56,57 with targeted therapies for BRCA carriers. As the de- and survival are needed. Future perspectives in this mand for TFGT increases, alternative models of providing field include the adoption of abbreviated MRI protocols and 442 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil TABLE 2. Recommendations for Testing Individuals With Hereditary Breast and Ovarian Cancer Individual without a cancer diagnosis should only be considered when an appropriate affected family member is unavailable for testing Individual from a family with a known BRCA1/2 pathogenic/likely pathogenic variant in a cancer predisposition gene Personal history of breast cancer and one of the following: Diagnosed at ≤ 45 years of age Diagnosed at 46-50 years of age with An additional breast cancer primary at any age ≥ 1 close blood relative with breast cancer at any age ≥ 1 close blood relative with high-grade (Gleason score ≥ 7) prostate cancer at any age An unknown or limited family history Diagnosed at ≤ 60 years of age with triple-negative breast cancer Diagnosed at any age with ≥ 1 close blood relative with Breast cancer diagnosed at ≤ 50 years of age; or Ovarian carcinoma, or Male breast cancer, or Metastatic prostate cancer, or Pancreatic cancer ≥ 2 additional diagnoses of breast cancer at any age in patient and/or in close blood relatives Personal history of male breast cancer Ashkenazi Jewish ancestry Personal history of ovarian carcinoma Personal history of pancreatic cancer Personal history of metastatic prostate cancer Personal history of high-grade prostate cancer (Gleason score ≥ 7) at any age with ≥ 1 close blood relative with ovarian carcinoma, pancreatic cancer, or metastatic prostate cancer at any age, or breast cancer at , 50 years of age ≥ 2 close blood relatives with breast or prostate cancer (any grade) at any age, or Ashkenazi Jewish ancestry BRCA1/2 pathogenic/likely pathogenic variant detected by tumor profiling on any tumor type in the absence of germline pathogenic/likely pathogenic variant analysis Regardless of family history, some individuals with a BRCA-related cancer may benefit from genetic testing to determine eligibility for targeted treatment An individual who does not meet the other criteria but with ≥ 1 first- or second-degree blood relative meeting any of the previously mentioned criteria; the significant limitations of interpreting test results for an unaffected individual should be discussed 58,59 the use of less contrast to reduce costs. OC screening is Contralateral Risk-Reducing Mastectomy for BRCA1 and not recommended. However, in patients who decline risk- BRCA2 Carriers reducing salpingo-oophorectomy, transvaginal ultrasound Cumulative contralateral BC risk 20 years after a first pri- and serum CA-125 may be considered, at the clinician’s mary BC is 40% for BRCA1 and 26% for BRCA2 carriers. discretion. Current evidence suggests that contralateral risk-reducing mastectomy is effective for BRCA1 carriers, reducing Risk-Reducing Bilateral Mastectomy for BRCA1 and 64-67 mortality. BRCA2 Carriers Bilateral mastectomy is associated with . 90% risk re- Risk-Reducing Bilateral Salpingo-Oophorectomy for duction in BC. In BRCA1 and BRCA2 carriers, nipple- BRCA1 and BRCA2 Carriers sparing mastectomy is associated with a low rate of 61,62 Bilateral salpingo-oophorectomy (BSO) confers a 72%- complications. Surveillance strategies after risk- 88% risk reduction in OC and fallopian tubal cancer. It is reducing mastectomy are not well established and associated with a reduction in OC-specific and all-cause should be addressed on a case-by-case basis. A recent 60,68 mortality in BRCA carriers. Therefore, BSO is recom- study showed that bilateral risk-reducing mastectomy in mended for BRCA carriers who have completed child- mutation carriers had an impact on mortality in BRCA1 bearing, and it should be performed by age 35-40 years in carriers, although the impact in BRCA2 carriers was less evident. BRCA1 carriers, by age 40-45 years in BRCA2 carriers, or JCO Global Oncology 443 Achatz et al 444 © 2020 by American Society of Clinical Oncology TABLE 3. Cancer Risk and Management in Non-BRCA Hereditary Breast and Ovarian Cancer–Related Genes Gene Breast Cancer Risk Breast Cancer Management Ovarian Cancer Risk Ovarian Cancer Management Other Cancer Risks ATM Increased risk Annual mammogram with consideration of Potentially Insufficient evidence for recommending Insufficient evidence for pancreas or tomosynthesis, and consider breast MRI with increased risk RRSO prostate cancer contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history BARD1 Potentially Insufficient evidence, manage on the basis of Unknown Insufficient evidence for management Unknown increased risk family history recommendations BRIP1 Unknown Insufficient evidence, manage on the basis of Increased risk Consider RRSO at age 45-50 years N/A family history CDH1 Increased risk Annual mammogram with consideration of No increased risk N/A Diffuse gastric cancer tomosynthesis, and consider breast MRI with contrast starting at age 30 years RRM: evidence insufficient, manage on the basis of family history CHEK2 Increased risk Annual mammogram with consideration of No increased risk N/A Colon cancer tomosynthesis, and consider breast MRI with contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history MLH1, MSH2 Unknown Insufficient evidence, manage on the basis of Increased risk Consider RRSO on completion of Colon, endometrial, and other cancers family history childbearing NBN Increased risk Annual mammogram with consideration of Unknown N/A Unknown tomosynthesis, and consider breast MRI with contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history NF1 Increased risk Annual mammogram with consideration of No increased risk N/A GIST, malignant peripheral nerve sheath tomosynthesis starting at age 30 years, and tumors, others consider breast MRI with contrast from ages 30-50 years RRM: evidence insufficient, manage on the basis of family history PALB2 Increased risk Annual mammogram with consideration of Unknown N/A Unknown tomosynthesis starting at age 30 years, and consider breast MRI at age 30 years RRM: evidence insufficient, manage on the basis of family history (Continued on following page) Recommendations for Hereditary Breast and Ovarian Cancer in Brazil JCO Global Oncology 445 TABLE 3. Cancer Risk and Management in Non-BRCA Hereditary Breast and Ovarian Cancer–Related Genes (Continued) Gene Breast Cancer Risk Breast Cancer Management Ovarian Cancer Risk Ovarian Cancer Management Other Cancer Risks PTEN Increased risk Annual mammogram with consideration of No increased risk N/A Thyroid, endometrial, renal, and colon tomosynthesis starting at age 30 years, and cancer consider breast MRI at age 30 years RRM: evidence insufficient, manage on the basis of family history RAD51C, Unknown Insufficient evidence, manage on the basis of Increased risk Consider RRSO at age 45-50 years Unknown RAD51D family history STK11 Increased risk Annual mammogram with consideration of Increased risk Insufficient evidence for management GI tumors tomosynthesis, and consider breast MRI with recommendations contrast starting at age 40 years RRM: evidence insufficient, manage on the basis of family history TP53 Increased risk Annual mammogram with consideration of No increased risk N/A Sarcomas, adrenocortical carcinoma, brain tomosynthesis, and consider breast MRI with tumors, and others contrast starting at age 25 years RRM: discuss option of risk-reducing mastectomy NOTE. Adapted from National Comprehensive Cancer Network. Abbreviations: GIST, gastrointestinal stromal tumor; MRI, magnet resonance imaging; N/A, not available; RRM, risk-reducing mastectomy; RRSO, risk-reducing salpingo-oophorectomy. Predisposes to lobular breast cancer. Mucinous ovarian cancer. Achatz et al 446 © 2020 by American Society of Clinical Oncology TABLE 4. Recommendations for Overcoming Barriers to Adequate Diagnosis and Management of Hereditary Breast and Ovarian Cancer in Brazil Access Barriers Education Barriers Quality Assurance Barriers Lack of a structured referral network in both public and private Limited public awareness of genetic risk and of the benefits of Lack of regulatory guidelines governing quality control of health care systems GCRA laboratories and genetic tests Insufficient number of trained professionals who are able to Incomplete/incorrect counseling provided by professionals with Lack of continued assessment of the quality of the clinical services recognize and provide genetic counseling to patients with limited knowledge in the field provided in cancer genetics a higher cancer risk Absence of genetic testing in the public system and limited access Limited knowledge of HBOC syndrome and tests among health Lack of adequate research budget for epidemiologic studies to for coverage in the private setting care professionals at all levels of care delineate hereditary cancer in the country Limited availability to genetic counseling in both public and Reluctance of at-risk patients and family members to seek genetic Lack of funding to develop innovative solutions to overcome local private systems testing and counseling barriers High cost of genetic tests Cultural and religious barriers Lack of inclusion of GCRA and surveillance of patients in the Patient and family fears and misconceptions national cancer policy Abbreviations: GCRA, genetic cancer risk assessment; HBOC, hereditary breast and ovarian cancer. Patients must fulfill Agencia Nacional de Saude criteria, including the need for a prescription from a board-certified clinical geneticist to qualify for reimbursement. Recommendations for Hereditary Breast and Ovarian Cancer in Brazil individualized, on the basis of the age of onset of OC in the MANAGEMENT OPTIONS FOR TP53 GERMLINE PATHOGENIC family. Detailed sectioning and microscopic examination of VARIANT CARRIERS ovaries and fallopian tubes from BSO in high-risk pop- All carriers of a TP53 pathogenic variant should receive ulations led to the identification of occult carcinomas in up intensive surveillance. In Brazil, because of the founder to 1.9%-9.1% of cases. After risk-reducing surgery, there variant present in a significant part of the population, is a 10% risk of recurrence after detection of an occult management is a public health situation that remains carcinoma and a 1% risk of developing a primary peritoneal unresolved. Nevertheless, breast MRI should be offered tumor. annually from age 20 years and mammography annually Early surgical castration causes early menopause and in- after age 30 years. Risk-reducing bilateral mastectomy creases the risk of cardiovascular disease and osteoporosis. and contralateral risk-reducing mastectomy should be On the basis of available data from observational studies, suggested. Whole-body MRI and brain MRI should be hormone replacement therapy after BSO should not be performed yearly from birth in carriers because of the high performed in patients affected by BC, but it has not shown risk of sarcomas and CNS, adrenocortical, and other an increased risk of BC among cancer-free BRCA carriers tumors. who have undergone risk-reduction bilateral mastectomy. COST-EFFECTIVENESS OF GENETIC TESTING Chemoprevention for BRCA1 and BRCA2 Carriers BRCA testing is cost effective in BC and OC. It is associated Large primary prevention trials with tamoxifen, 20 mg once with reduced risk and improved survival in female carriers, per day for 5 years, have demonstrated that BC risk can be with benefits when testing is extended to family members reduced by 40%-50% in women at high risk, although not 79,80 (cascade testing). Presymptomatic cancer surveillance necessarily in pathogenic variant carriers. Limited data is cost effective for patients with germline pathogenic are available regarding the benefit of tamoxifen in BRCA variants in TP53. carriers, but it may be considered for patients who do not 72,73 want to undergo risk-reducing surgery. There are no Risk-reduction surgery and intensive breast screening data on the benefit of raloxifene or aromatase inhibitors in were cost effective in models of BRCA carrier risk BRCA carriers. management. In Brazil, BRCA1/BRCA2 diagnostic and management strategies for patients with OC were consid- PolyADP-Ribose Polymerases in BRCA-Associated OC for ered cost effective but only when cancer-unaffected rel- BRCA1 and BRCA2 Carriers atives of OC mutation carriers were included in the PolyADP-ribose polymerases (PARP) inhibitor is a targeted model. therapy that acts on a deficiency in the HR pathway. In OC, 2 randomized phase III trials (SOLO-2 and NOVA) CURRENT BARRIERS AND RECOMMENDATIONS FOR demonstrated improved progression-free survival with OVERCOMING BARRIERS TO ADEQUATE DIAGNOSIS AND monotherapy PARP inhibitor as maintenance therapy MANAGEMENT OF HBOC IN BRAZIL in patients with recurrent, platinum-sensitive BRCA- Despite evidence of the benefits of genetic counseling, 74,75 associated OC and HR-deficient tumors. In first-line testing, and adequate risk management, access is limited treatment, SOLO-1 showed better progression-free survival in Brazil and in most Latin American countries (Table 4). To with PARP inhibitor (olaparib) maintenance treatment after address these limitations, strategies related to public usual chemotherapy in BRCA-associated stage III-IV high- awareness, education, integrated services, implementa- grade serous or endometrial OC. Agencia Nacional de tion, and monitoring are needed. Government, medical ˆ ´ Vigilancia Sanitaria has approved olaparib for relapsed societies, patient organizations, academic centers, and the high-grade OC and for first-line BRCA-associated serous private sector should create a multistakeholder commission and endometrioid high-grade OC, but it is not yet available to develop and promote the incorporation of GCRA and to the public or in the private health system. management into the public and private health care sys- PARP Inhibitor in BRCA-Associated BC for BRCA1 and tems. Such a plan should include the following: BRCA2 Carriers 1. Establishment of genetic health benefits, including Two phase III trials (OlympiAD and EMBRACA) randomly genetic testing, counseling, and long-term manage- assigned patients after chemotherapy in HER2-negative, ment, accessible to patients in both public and private BRCA-associated metastatic BC and showed longer health care systems: progression-free survival with PARP inhibitor. The Food � The Brazilian National Cancer Control Policy should and Drug Administration has approved 2 PARP inhibi- be updated to include essential genetic health 77 78 tors (olaparib and talazoparib ) for germline BRCA- benefits. associated metastatic BC. In Brazil, olaparib was ap- � Regulatory agencies in the Brazilian Ministry of ˆ ˆ proved in this setting by Agencia Nacional de Vigilancia Health should prioritize the incorporation of policies Sanitaria in 2018. related to hereditary cancer. JCO Global Oncology 447 Achatz et al � Guidelines that ensure coverage for genetic services 6. A Brazilian network of reference centers should be in private health care should be updated on an expanded and the insertion of GCRA and genetic annual basis and should include genetic testing testing should be championed in both public and coverage for cancer-unaffected individuals when private health care systems. first- and second-degree relatives fulfill criteria. 7. Continuing professional education and periodic 2. Development of a 3-tiered training program for health recertification should be implemented to guarantee professionals. clinical and laboratory services. Professional societies � Tier 1: Basic genetics education and continued should oversee these efforts. medical education should be provided to all health 8. Government, medical societies, health care pro- care professionals to enable recognition and referral fessionals, and patient organizations should support of at-risk patients; education programs to promote public awareness of � Tier 2: A minimum curriculum on hereditary cancer the importance of understanding personal and family should be included in training programs in spe- genetic risk factors and their influence on cancer cialties related to cancer care, and continuing management. medical education should be required; 9. Politicians should be encouraged to pass laws pro- � Tier 3: Specialty training programs should be de- tecting individuals against genetic discrimination by veloped and expanded for health care professionals employers and insurance companies. seeking to conduct GCRA. 10. Systematic reporting should be encouraged. Results 3. In TFGT, a streamlined approach should be imple- from clinical and research-focused genetic testing mented. Traditional GCRA should be available when- should be made available in public databases on ever indicated. Research studies should be conducted human genomic variations. to validate whether a streamlined approach is effective There is a great need to expand hereditary cancer testing in Brazil. and counseling in Brazil. Understanding Brazil’s unique 4. Genetic counseling and risk assessment should be social and structural barriers and mounting a strong, timely offered in a multidisciplinary setting involving multiple response to this public health problem is crucial. Increased health care professionals to ensure the most appro- knowledge and awareness of HBOC among nongenetic priate management of patients and their families. health care professionals, as well as the general population, 5. Public health officials should be educated on the public health officials, and patient organizations, would importance of GCRA, guaranteeing access to genetic health benefits as part of the strategic national cancer advance translational efforts to improve cancer care and control plan. outcomes. AFFILIATIONS SUPPORT ´ ˆ Centro de Oncologia, Hospital Sırio-Libanes, São Paulo, Brazil Supported by a grant from the Americas Health Foundation, a 501(c)(3) Nucleo Mama Porto Alegre and Associação Hospitalar Moinhos de nonprofit organization dedicated to improving health care throughout the Vento, Porto Alegre, Brazil Latin American Region, and by an unrestricted grant from AstraZeneca. Oncologia D’or, Rede D’or São Luiz, Brazil Centro de Investigação Translacional em Oncologia, Instituto do Cancer AUTHOR CONTRIBUTIONS do Estado de Sao Paulo, Hospital das Clınicas da Faculdade de Medicina Conception and design: All authors da Universidade de Sao Paulo, São Paulo, Brazil Provision of study material or patients: Maira Caleffi Programa da Saude da Mulher, Hospital Israelita Albert Einstein, São Collection and assembly of data: Rodrigo Guindalini, Paulo, Brazil Patricia Ashton-Prolla Centro de Oncologia e Hematologia, Hospital Israelita Albert Einstein, Data analysis and interpretation: Rodrigo Guindalini, São Paulo, Brazil Patricia Ashton-Prolla Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Manuscript writing: All authors Grupo Brasileiro de Oncologia Ginecologica, ´ Belo Horizonte, Brazil Final approval of manuscript: All authors DOM Oncologia, Minas Gerais, Brazil Accountable for all aspects of the work: All authors Departmento de Genetica, ´ Universidade Federal do Rio Grande do Sul Laboratorio ´ de Medicina Genomic ˆ a, Hospital de Cl´ınicas de Porto AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF Alegre, Porto Alegre, Brazil INTEREST The Americas Health Foundation had no role in deciding the content of The following represents disclosure information provided by authors of this article, and the recommendations are those solely of the panel this manuscript. All relationships are considered compensated unless members. otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the CORRESPONDING AUTHOR subject matter of this manuscript. For more information about ASCO’s Maria Isabel Achatz, MD, PhD, Rua Dona Adma Jafet 115, São Paulo, SP conflict of interest policy, please refer to www.asco.org/rwc or ascopubs. Brazil, 01308-060; Twitter: @AchatzIsabel; e-mail: miachatz@ org/go/site/misc/authors.html. gmail.com. 448 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil Open Payments is a public database containing information reported by Speakers’ Bureau: AstraZeneca, Roche, MSD, Bayer, Merck, Teva, companies about payments made to US-licensed physicians (Open Boehringer Ingelheim, Bristol-Myers Squibb Payments). Travel, Accommodations, Expenses: AstraZeneca, Roche Maria Isabel Achatz Angelica Nogueira-Rodrigues Speakers’ Bureau: AstraZeneca, MSD Oncology Honoraria: Roche, MSD, AstraZeneca Consulting or Advisory Role: Roche, AstraZeneca, MSD, Eisai Rodrigo Guindalini Patricia Ashton-Prolla Employment: CLION, Grupo CAM, Oncologia D’or Stock and Other Ownership Interests: Mendelics Analise ´ Genomica ˆ Research Funding: AstraZeneca Brazil (Inst) Consulting or Advisory Role: AstraZeneca Brazil, Merck Brazil No other potential conflicts of interest were reported. REFERENCES 1. Szabo CI, King MC: Inherited breast and ovarian cancer. Hum Mol Genet 4:1811-1817, 1995 2. Roy R, Chun J, Powell SN: BRCA1 and BRCA2: Different roles in a common pathway of genome protection. Nat Rev Cancer 12:68-78, 2011 3. Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003 4. Mersch J, Jackson MA, Park M, et al: Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121:269-275, 2015 5. Kuchenbaecker KB, Hopper JL, Barnes DR, et al: Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402-2416, 2017 6. Risch HA, McLaughlin JR, Cole DE, et al: Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: A kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98:1694-1706, 2006 7. Kalia SS, Adelman K, Bale SJ, et al: Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): A policy statement of the American College of Medical Genetics and Genomics. Genet Med 19:249-255, 2017 [Erratum: Genet Med, 2017] 8. Peters ML, Garber JE, Tung N: Managing hereditary breast cancer risk in women with and without ovarian cancer. Gynecol Oncol 146:205-214, 2017 9. Graffeo R, Livraghi L, Pagani O, et al: Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat 160:393-410, 2016 10. Buys SS, Sandbach JF, Gammon A, et al: A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 123:1721-1730, 2017 11. Eliade M, Skrzypski J, Baurand A, et al: The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? Oncotarget 8:1957-1971, 2017 12. Robson M, Domchek S: Broad application of multigene panel testing for breast cancer susceptibility-Pandora’s box is opening wider. JAMA [epub ahead of print on October 3, 2019] 13. Meiser B, Quinn VF, Gleeson M, et al: When knowledge of a heritable gene mutation comes out of the blue: Treatment-focused genetic testing in women newly diagnosed with breast cancer. Eur J Hum Genet 24:1517-1523, 2016 14. Rebbeck TR, Mitra N, Wan F, et al: Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313:1347-1361, 2015 ´ ´ 15. Baquero JM, Benıtez-Buelga C, Fernandez V, et al: A common SNP in the UNG gene decreases ovarian cancer risk in BRCA2 mutation carriers. Mol Oncol 13:1110-1120, 2019 16. Rebbeck TR, Friebel TM, Friedman E, et al: Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593-620, 2018 17. Carraro DM, Koike Folgueira MA, Garcia Lisboa BC, et al: Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: A portrait of early-onset breast cancer in Brazil. PLoS One 8:e57581, 2013 18. Silva FC, Lisboa BC, Figueiredo MC, et al: Hereditary breast and ovarian cancer: Assessment of point mutations and copy number variations in Brazilian patients. BMC Med Genet 15:55, 2014 19. Fernandes GC, Michelli RA, Galvão HC, et al: Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget 7:80465-80481, 2016 20. Maistro S, Teixeira N, Encinas G, et al: Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer 16:934, 2016 21. Alemar B, Herzog J, Brinckmann Oliveira Netto C, et al: Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet 209:417-422, 2016 22. Alemar B, Gregorio ´ C, Herzog J, et al: BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? PLoS One 12:e0187630, 2017 [Erratum: PLoS One, 2018] 23. Palmero EI, Carraro DM, Alemar B, et al: The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep 8:9188, 2018 24. de Souza Timoteo AR, Gonçalves AEMM, Sales LAP, et al: A portrait of germline mutation in Brazilian at-risk for hereditary breast cancer. Breast Cancer Res Treat 172:637-646, 2018 25. Felix GE, Abe-Sandes C, Machado-Lopes TM, et al: Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: Characterizing a Northeast Brazilian Population. Hum Genome Var 1:14012, 2014 26. National Comprehensive Cancer Network: NCCN guidelines. https://www.nccn.org/professionals/physician_gls/default.aspx 27. Agencia Nacional de Saude: Resolução Normativa – RN N° 428 de 7 de Novembro deo 2017. http://www.ans.gov.br/component/legislacao/?view=legislacao& task=PDFAtualizado&format=raw&id=MzUwMg== 28. Salzano FM, Bortolini MC: The Evolution and Genetics of Latin American Populations. Cambridge, UK, Cambridge University Press, 2002 29. Pena SD, Di Pietro G, Fuchshuber-Moraes M, et al: The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One 6:e17063, 2011 30. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al: A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358-5362, 1988 31. Børresen-Dale AL: TP53 and breast cancer. Hum Mutat 21:292-300, 2003 JCO Global Oncology 449 Achatz et al 32. Olivier M, Langerød A, Carrieri P, et al: The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157-1167, 33. Silwal-Pandit L, Vollan HK, Chin SF, et al: TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 20:3569-3580, 2014 34. Mai PL, Khincha PP, Loud JT, et al: Prevalence of cancer at baseline screening in the National Cancer Institute Li-Fraumeni syndrome cohort. JAMA Oncol 3:1640-1645, 2017 35. Masciari S, Dillon DA, Rath M, et al: Breast cancer phenotype in women with TP53 germline mutations: A Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat 133:1125-1130, 2012 36. Mastellaro MJ, Seidinger AL, Kang G, et al: Contribution of the TP53 R337H mutation to the cancer burden in southern Brazil: Insights from the study of 55 families of children with adrenocortical tumors. Cancer 123:3150-3158, 2017 37. Achatz MI, Zambetti GP: The inherited p53 mutation in the Brazilian population. Cold Spring Harb Perspect Med 6:a026195, 2016 38. Giacomazzi J, Graudenz MS, Osorio CA, et al: Prevalence of the TP53 p.R337H mutation in breast cancer patients in Brazil. PLoS One 9:e99893, 2014 39. Chompret A, Abel A, Stoppa-Lyonnet D, et al: Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38:43-47, 2001 40. Andrade KC, Santiago KM, Fortes FP, et al: Early-onset breast cancer patients in the south and southeast of Brazil should be tested for the TP53 p.R337H mutation. Genet Mol Biol 39:199-202, 2016 41. Hahn EC, Bittar CM, Vianna FSL, et al: TP53 p.Arg337His germline mutation prevalence in southern Brazil: Further evidence for mutation testing in young breast cancer patients. PLoS One 13:e0209934, 2018 42. Weitzel JN, Blazer KR, MacDonald DJ, et al: Genetics, genomics and cancer risk assessment: State of the art and future directions in the era of personalized medicine. CA Cancer J Clin 61:327-359, 2011 43. Quinn VF, Meiser B, Kirk J, et al: Streamlined genetic education is effective in preparing women newly diagnosed with breast cancer for decision making about treatment-focused genetic testing: A randomized controlled noninferiority trial. Genet Med 19:448-456, 2017 44. Colombo N, Huang G, Scambia G, et al: Evaluation of a streamlined oncologist-led BRCA mutation testing and counseling model for patients with ovarian cancer. J Clin Oncol 36:1300-1307, 2018 45. Copson ER, Maishman TC, Tapper WJ, et al: Germline BRCA mutation and outcome in young-onset breast cancer (POSH): A prospective cohort study. Lancet Oncol 19:169-180, 2018 46. Slavin TP, Manjarrez S, Pritchard CC, et al: The effects of genomic germline variant reclassification on clinical cancer care. Oncotarget 10:417-423, 2019 47. Easton DF, Pharoah PD, Antoniou AC, et al: Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372:2243-2257, 2015 48. Crawford B, Adams SB, Sittler T, et al: Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients. Breast Cancer Res Treat 163:383-390, 2017 49. Mersch J, Brown N, Pirzadeh-Miller S, et al: Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA 320:1266-1274, 2018 50. Kuhl C, Weigel S, Schrading S, et al: Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: The EVA trial. J Clin Oncol 28:1450-1457, 2010 51. Le-Petross HT, Whitman GJ, Atchley DP, et al: Effectiveness of alternating mammography and magnetic resonance imaging for screening women with deleterious BRCA mutations at high risk of breast cancer. Cancer 117:3900-3907, 2011 52. Riedl CC, Luft N, Bernhart C, et al: Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density. J Clin Oncol 33:1128-1135, 2015 53. Phi XA, Saadatmand S, De Bock GH, et al: Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: Individual patient data meta-analysis. Br J Cancer 114:631-637, 2016 54. Saslow D, Boetes C, Burke W, et al: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57:75-89, 2007 55. Guindalini RSC, Zheng Y, Abe H, et al: Intensive surveillance with biannual dynamic contrast-enhanced magnetic resonance imaging downstages breast cancer in BRCA1 mutation carriers. Clin Cancer Res 25:1786-1794, 2019 56. Pijpe A, Andrieu N, Easton DF, et al: Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: Retrospective cohort study (GENE-RAD-RISK). BMJ 345:e5660, 2012 57. Plevritis SK, Kurian AW, Sigal BM, et al: Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA 295:2374-2384, 2006 58. Pataky R, Armstrong L, Chia S, et al: Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers. BMC Cancer 13:339, 2013 59. Kuhl CK, Schrading S, Strobel K, et al: Abbreviated breast magnetic resonance imaging (MRI): First postcontrast subtracted images and maximum-intensity projection-a novel approach to breast cancer screening with MRI. J Clin Oncol 32:2304-2310, 2014 60. Ludwig KK, Neuner J, Butler A, et al: Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review. Am J Surg 212:660-669, 2016 61. Yao K, Liederbach E, Tang R, et al: Nipple-sparing mastectomy in BRCA1/2 mutation carriers: An interim analysis and review of the literature. Ann Surg Oncol 22:370-376, 2015 [Erratum: Ann Surg Oncol 21:S788, 2014] 62. Jakub JW, Peled AW, Gray RJ, et al: Oncologic safety of prophylactic nipple-sparing mastectomy in a population with BRCA mutations: A multi-institutional study. JAMA Surg 153:123-129, 2018 63. Heemskerk-Gerritsen BAM, Jager A, Koppert LB, et al: Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 177:723-733, 2019 64. Boughey JC, Hoskin TL, Degnim AC, et al: Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer. Ann Surg Oncol 17:2702-2709, 2010 65. Lostumbo L, Carbine NE, Wallace J: Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 11:CD002748, 2010 66. Metcalfe K, Gershman S, Ghadirian P, et al: Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: Ret- rospective analysis. BMJ 348:g226, 2014 67. Evans DG, Ingham SL, Baildam A, et al: Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer. Breast Cancer Res Treat 140:135-142, 2013 68. George SH, Shaw P: BRCA and early events in the development of serous ovarian cancer. Front Oncol 4:5, 2014 69. Powell CB, Chen LM, McLennan J, et al: Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: Experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol. Int J Gynecol Cancer 21:846-851, 2011 450 © 2020 by American Society of Clinical Oncology Recommendations for Hereditary Breast and Ovarian Cancer in Brazil 70. Kotsopoulos J, Gronwald J, Karlan BY, et al: Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA Oncol 4:1059-1065, 2018 71. Cuzick J, Sestak I, Bonanni B, et al: Selective oestrogen receptor modulators in prevention of breast cancer: An updated meta-analysis of individual participant data. Lancet 381:1827-1834, 2013 72. King MC, Wieand S, Hale K, et al: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286:2251-2256, 2001 73. Phillips KA, Milne RL, Rookus MA, et al: Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol 31:3091-3099, 74. Pujade-Lauraine E, Ledermann JA, Selle F, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18:1274-1284, 2017 75. Mirza MR, Monk BJ, Herrstedt J, et al: Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375:2154-2164, 2016 76. Moore K, Colombo N, Scambia G, et al: Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379:2495-2505, 2018 77. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017 [Erratum: N Engl J Med, 2017] 78. Litton JK, Rugo HS, Ettl J, et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753-763, 2018 79. Tuffaha HW, Mitchell A, Ward RL, et al: Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers. Genet Med 20:985-994, 2018 80. Eccleston A, Bentley A, Dyer M, et al: A cost-effectiveness evaluation of germline BRCA1 and BRCA2 testing in UK women with ovarian cancer. Value Health 20:567-576, 2017 81. Tak CR, Biltaji E, Kohlmann W, et al: Cost-effectiveness of early cancer surveillance for patients with Li-Fraumeni syndrome. Pediatr Blood Cancer 66:e27629, 82. Muller ¨ D, Danner M, Schmutzler R, et al: Economic modeling of risk-adapted screen-and-treat strategies in women at high risk for breast or ovarian cancer. Eur J Health Econ 20:739-750, 2019 83. Ramos MCA, Folgueira MAAK, Maistro S, et al: Cost effectiveness of the cancer prevention program for carriers of the BRCA1/2 mutation. Rev Saude Publica 52:94, 2018 84. Mitropoulos K, Al Jaibeji H, Forero DA, et al: Success stories in genomic medicine from resource-limited countries. Hum Genomics 9:11, 2015 85. Laraqui A, Uhrhammer N, Rhaffouli HE, et al: BRCA genetic screening in Middle Eastern and North African: Mutational spectrum and founder BRCA1 mutation (c.798_799delTT) in North African. Dis Markers 2015:194293, 2015 86. Seymour HJ, Wainstein T, Macaulay S, et al: Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient? S Afr Med J 106:264-267, 2016 ´ ´ 87. Villarreal-Garza C, Alvarez-Gomez RM, Perez-Plasencia C, et al: Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico. Cancer 121:372-378, 2015 88. Cavallone L, Arcand SL, Maugard CM, et al: Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer 9:507-517, 2010 89. Manchanda R, Loggenberg K, Sanderson S, et al: Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: A randomized controlled trial. J Natl Cancer Inst 107:379, 2014 90. Peixoto A, Santos C, Pinheiro M, et al: International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation. Breast Cancer Res Treat 127:671-679, 2011 91. Rafnar T, Benediktsdottir KR, Eldon BJ, et al: BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: A population-based study. Eur J Cancer 40:2788-2793, 2004 92. Van Der Looij M, Szabo C, Besznyak I, et al: Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary. Int J Cancer 86:737-740, 2000 nn n JCO Global Oncology 451 Achatz et al APPENDIX TABLE A1. Breast Cancer Risk and Protective Factors Nongenetic Exposures Variable Hereditary Ovarian Cancer Risk Factor b c Late age at menarche BRCA1: Null results or borderline protective effect b,d BRCA2: null results Alcohol consumption Three studies reported on alcohol use, all of which reported null results Smoking BRCA1: One article studied coffee intake and smoking with null results in each category f,g BRCA2: A pooled estimate of 2 studies showed an increased risk for more than 4 years of smoking v never, whereas an ever v never meta-analysis of smoking produced null results Coffee/caffeine intake BRCA1: One article studied coffee intake and smoking, with null results in each category Oral contraceptive use BRCA1: Studies reported a decreased risk of ovarian cancer for BRCA1 mutation carriers with ever v never use; when the oral contraceptive use occurred for . 1 year, there was a statistically significant b,c,h,i decreased risk, ranging from a 33% to a 80% reduction BRCA2: Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA2 mutations (0.39 h-j [0.23-0.66]; P = .0004) b,k,l Age at first live birth BRCA1/2: The meta-analysis results were largely null Parity BRCA1/2: Studies reported on trend per birth, and a meta-analysis showed statistically significant risk b,c,i,l reduction only seen in women with . 4 live births Breastfeeding BRCA1: A study reported a statistically significant reduction in ovarian cancer risk with ever v never breastfeeding. b,j BRCA2: Two studies reported no association for ever v never, ≤ 1 year v never, and . 1 year v never i,m Combined HRT exposure BRCA1: Hormone replacement therapy was examined, with null effects reported Tamoxifen (contralateral breast cancer) BRCA1: One study reported a null effect of tamoxifen i,n BRCA2: Studies reported a null effect b,h,j Tubal ligation BRCA1: Studies that evaluated tubal ligation reported a reduction in risk for ever having a tubal ligation b,h,j BRCA2: No protective effect of tubal ligation was seen among carriers of the mutation NOTE. Boldface indicates significance. Abbreviation: HRT, hormone replacement therapy. Friebel TM, Domchek SM, Rebbeck TR: Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: Systematic review and meta-analysis. J Natl Cancer Inst 106:dju091, 2014. Antoniou AC, Rookus M, Andrieu N, et al: Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: Results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 18:601-610, 2009. Gronwald J, Byrski T, Huzarski T, et al: Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Res Treat 95:105-109, 2006. Park B, Hopper JL, Win AK, et al: Reproductive factors as risk modifiers of breast cancer in BRCA mutation carriers and high-risk non-carriers. Oncotarget 8:102110-102118, 2017. McGuire V, John EM, Felberg A, et al: No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages ,50 years. Cancer Epidemiol Biomarkers Prev 15:1565-1567, 2006. Breast Cancer Family Registry; Kathleen Cuningham Consortium for Research into Familial Breast Cancer (Australasia); Ontario Cancer Genetics Network (Canada): Smoking and risk of breast cancer in carriers of mutation in BRCA1 or BRCA2 aged less than 50 years. Breast Cancer Res Treat 109:67-75, 2008. Ginsburg O, Ghadirian P, Lubinski J, et al: Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: An update. Breast Cancer Res Treat 114:127-135, 2009. Narod SA, Sun P, Ghadirian P, et al: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: A case-control study. Lancet 357:1467-1470, 2001. Vicus D, Rosen B, Lubinski J, et al: Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers. Gynecol Oncol 115:135-137, 2009. McLaughlin JR, Risch HA, Lubinski J, et al: Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: A case-control study. Lancet Oncol 8:26-34, 2007. Lecarpentier J, Nogues C, Mouret-Fourme E, et al: Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO). Breast Cancer Res 14:R99, 2012. Milne RL, Osorio A, Ramon y Cajal T, et al: Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119:221-232, 2010. Kotsopoulos J, Lubinski J, Neuhausen SL, et al: Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Gynecol Oncol 100:83-88, 2006. Phillips K-A, Milne RL, Bassett JK, et al: Tamoxifen and contralateral breast cancer (CBC) risk for BRCA1 and BRCA2 mutation carriers: An updated analysis of data from the Kathleen Cuningham Foundation consortium for research into familial breast cancer, the International BRCA1 and BRCA2 carrier cohort study and the breast cancer family registry. Cancer Res 78, 2018 (abstr). 452 © 2020 by American Society of Clinical Oncology

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JCO Global OncologyPubmed Central

Published: Mar 10, 2020

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