Artigo Científico Ca de Mama

Clinical Oncology 37 2025 103658 Original Article Breast Cancer Prognosis in Young BRCA1BRCA2 Mutation Carriers A Retrospective Hospitalbased Cohort Study F Hego M Barthoulot S Chretien C Pierard M Boulaire S Bécourt L Boulanger L Ceugnart AL Conoy F Oca A Mailliez Department of Medical Oncology Breast Cancer Unit Lille Oscar Lambret Center 3 rue Frédéric Combemale 59020 Lille France Lille University Faculty of Medicine Henri Warembourg 2 Av Eugène Avinée 59120 Loos France Department of Biostatistics Lille Oscar Lambret Center 3 rue Frédéric Combemale 59020 Lille France Department of Surgical Oncology Breast Cancer Unit Lille Oscar Lambret Center 3 rue Frédéric Combemale 59020 Lille France Department of Imaging Lille Oscar Lambret Center 3 rue Frédéric Combemale 59020 Lille France Department of Biopathology Human Molecular Oncogenetic Unit Lille Oscar Lambret Center 3 rue Frédéric Combemale 59020 Lille France Abstract Aim Studies evaluating the prognostic impact of germline BRCA12 mutations gBRCAm in patients with breast cancer report conflicting results Therefore we aimed to investigate outcomes of patients with gBRCA mutations and early onset of breast cancer 30 years compared with those of noncarriers Materials and methods This retrospective study included 149 patients recruited between 2005 and 2019 The outcomes were overall survival OS and diseasefree survival DFS which were defined as the time from the first diagnosis to death from any cause and the first recurrence second cancer or death from any cause respectively Key patient data KaplanMeier plots and outcomes were described according to the BRCA mutation status Hazard ratios HR were calculated using the Cox proportional hazards model Results Twentyeight patients 28149 188 were gBRCAm carriers The OS median followup was 82 years OS was 893 704964 in carriers vs 992 95 CI 943999 in noncarrier patients at 2 years 852 652942 vs 930 865965 at 5 years and 765 547888 vs 852 757912 at 10 years There was no difference in OS between groups in multivariable analysis HR 190 069523 p 022 The DFS median followup was 66 years Similar results were observed for DFS HR 139 063308 p 042 Conclusion In this large hospitalbased cohort of patients with very earlyonset breast cancer we found no clear evidence that gBRCA12m significantly affects OS after adjusting for known prognostic factors 2024 The Royal College of Radiologists Published by Elsevier Ltd All rights are reserved including those for text and data mining AI training and similar technologies Keywords Early breast cancer germline BRCA mutation prognosis survival young women Introduction Globally breast cancer is the most common cancer in women mostly diagnosed in women over 50 years of age 1 Moreover approximately 05 of all breast cancer cases occur before 30 years of age In France approximately 300 women aged 30 years old are diagnosed with breast cancer annually Germline pathogenic variants of the BRCA1 and BRCA2 genes gBRCAm account for approximately 5 of breast cancers 2 but increases up to 620 among women younger than 30 years old 3 Consequently understanding the prognosis of patients with very youngonset breast cancer is relevant because they are more likely to carry deleterious gBRCAm than their older counterparts Additionally young women are more likely to develop breast cancer with worse clinicopathological features and more aggressive subtypes leading to a higher proportion of deaths from breast cancer and more frequent secondary cancers during followup 4 However limited data are available regarding young patients 30 years old treated for earlystage breast cancer Moreover studies evaluating the prognostic impact of gBRCAm in patients with breast cancer have reported controversial results however the outcomes appear to be similar to those of sporadic breast cancer after adjusting for tumor and patient characteristics 56 A prospective study of patients with breast cancer aged 40 years showed no differences in survival outcomes between gBRCAm carriers and noncarriers However the authors stated that gBRCAm carriers with triplenegative breast cancer might have a survival advantage during the first few years after diagnosis than noncarriers 6 Conversely another retrospective study focusing on women aged 50 years showed worse survival during the first five years of followup among gBRCA1 mutation carriers 7 In the case of gBRCAm active presymptomatic identification of carriers is proposed for relatives and specific screening and prevention strategies are dedicated to gBRCAm carriers According to French recommendations 8 women 30 years old must undergo annual clinical examinations including yearly breast imaging screening with breast MRI and mammography at the age of 30 years The age for initiation of breast imaging screening was set at 30 years representing the threshold at which the risk of gBRCAm carriers with breast cancer significantly increases compared to noncarrier patients However some patients are treated for very earlyonset breast cancer 30 years old Therefore a deeper understanding of the characteristics and prognosis of these patients and the impact of BRCA germline mutations could lead to modifications in the screening procedures Although gBRCA12m is a wellestablished risk factor for primary breast cancer 2 whether these mutations are independent prognostic factors after an initial very early diagnosis are unclear Thus we aimed to analyze the effect of gBRCA mutations on survival outcomes in a retrospective cohort of patients with very early onset of breast cancer compared to noncarriers Materials and Methods Population This retrospective cohort study included women referred for genetic counseling at the Oscar LAMBRET center Women were eligible if they were aged 30 years and diagnosed with invasive breast cancer between January 1 2005 and December 31 2019 and underwent genetic testing for BRCA1 and BRCA2 germline mutations The exclusion criteria were male sex local locoregional or metastatic recurrence after initial breast cancer treatment before 2005 and de novo metastatic breast cancer This study was approved by the Oscar LAMBRET center Institutional Review Board and was conducted in accordance with French Regulations MR004 As this study was not interventional no signed consent was requested however the nonobjection of patients to the use of their data were checked Data Collection Clinical Characteristics Genetic Testing Methods and Treatment Data on patient and clinical characteristics family history tumor pathology disease stage treatment and followup data were retrospectively collected from medical records The information on the death was obtained from hospital records and supplemented by public national mortality data published by INSEE the French Institute of Statistics and Economic Studies Personal and clinical characteristics collected included age at diagnosis laterality cTNM uni or multifocality menarche number of pregnancies age at first birth parity use of hormonal contraception weight height body mass index BMI and physical activity intensity Physical activity data were collected using a selfadministered questionnaire before oncogenetic consultation Family history of breast 1st 2nd or 3rd degree age at diagnosis ovarian 1st or 2nd degree and pancreatic cancer and melanoma were also recorded Tumor characteristics collected were histological type ScarffBloomRichardson grade breast cancer human epidermal growth factor receptor 2 HER2 hormone receptor HR status derived from surgical breast tumor sample Ki 67 levels pTNM or ypTNM if available Tumors were defined as hormone receptorpositive HR if estrogen receptor ER or progesterone receptor PR expression was 10 based on immunohistochemistry An HER2 immunohistochemical IHC score of 3 or 2 with positive fluorescence in situ hybridization FISH or chromogenic in situ hybridization CISH classified the cancer as HER2positive All cancers with an IHC score of 01 or 2 with a negative FISHCISH test as well as cancers with a negative FISHCISH test without IHC information were considered HER2negative HER2 Breast cancer was categorized based on the following three subtypes HRpositiveHER2negative HRHER2 HER2positive and triplenegative breast cancer TNBC Germline BRCA status mutation type and germline mutation diagnostic techniques were collected Sequencing technologies evolved during the studied period Sanger sequencing was used until May 2014 Since June 2014 next generation sequencing analyses were conducted for all patients Detection of large genomic rearrangements was performed by multiplex ligationdependent probe amplification Additionally the type of breast and axillary surgery setting and protocols for chemotherapy radiation endocrine therapy trastuzumab use and prophylactic surgery were recorded Objectives The primary objective of this study was to compare the overall survival OS of patients 30 years old with gBRCAm breast cancer versus noncarriers The secondary objectives were to compare the invasive diseasefree survival DFS between gBRCAm carriers and noncarriers and to assess the clinical and pathological characteristics treatments personal risk factors for breast cancer and family history of cancer in the two groups Statistical Analyses Categorical variables are described as numbers and proportions 95 confidence interval CI Continuous variables are summarized using medians and ranges Pa tient baseline characteristics and clinicopathological data were described by BRCA mutation status and compared using ManneWhitney tests for continuous variables and Pearson c2 tests for categorical variables Overall survival OS was defined as the time from diagnosis to death from any cause with followup ending at either the date of death or the last INSEE consultation 02 012022 DFS was defined as the time from diagnosis to the first recurrence second cancer or death from any cause with followup ending at the date of the event documented in the medical record thus excluding deaths known through INSEE or the last recorded medical followup in the absence of an event OS and DFS were estimated using the KaplaneMeier method Patients alive at their last followup were censored Two estimations of the median followup period were performed using the inverse KaplaneMeier method Schemper The first from diagnosis to the last followup date use for OS and the second from diagnosis to the last followup date use for DFS KaplaneMeier plots were used to present survival data according to BRCA status at 2 5 and 10 years These time points were selected because they are commonly used in such studies and are clinically relevant To investigate the association between overall survival OS and DFS dependent variables and BRCA mutation status main independent variable we constructed two models Other independent variables included BMI clin ical tumor and lymph node stage tumor grade hormone receptor status HER2 triplenegative and Ki67 Associa tions were first tested univariately Then two multivariate Cox models were constructed including variables that were significant p 020 clinically relevant and with less than 5 missing data In the OS model the triple negative variable did not meet the proportional hazards assumption so we stratified the model on this variable The limited number of events N ¼ 24 also forced us to combine tumor and lymph node stages into a composite variable The final model was therefore adjusted on this composite variable and tumor grade with stratification on triplenegative status For DFS all variables met the pro portional hazards assumption With a higher number of events we were able to adjust the final model on clinical tumor and lymph node stages tumor grade and triple negative status All tests were performed with a two sided alpha level of 005 Estimates are provided with 95 confidence intervals 95 CIs Analyses were per formed using the STATA software version 170 StataCorp LLC College Station TX USA Results Comparison of Clinicopathological Characteristics Between gBRCAm Carriers and Noncarriers In total149 patients with breast cancer diagnosed before the age of 30 and referred for genetic counseling were included Of the 149 patients 121 tested negative for mu tations in the gBRCA1 and gBRCA2 genes hereafter non carriers and 28 188 were found to carry a gBRCA12 mutation hereafter carriers The patient characteristics are summarized in Table 1 Most patients presented with invasive ductal carcinoma while only one patient presented with micropapillary carcinoma gBRCA noncarriers were more likely to have grade I or II disease p ¼ 0015 stage N0 disease p ¼ 0011 hormone receptorpositive status p ¼ 0011 and HER2positive p 001 tumors than gBRCA carriers Additionally gBRCA carriers were more likely to have triplenegative tumors p 001 Clinical tumor stage and Ki67 were not significantly different between the two groups Moreover no differences in the known risk factors for breast cancer young age at first periods no history of pregnancy old age at first pregnancy high BMI were noted between the two groups Regarding family history of cancer we noted an increased proportion of breast cancers in 2nd degree relatives p¼ 0006 breast cancers before 35 years of age p ¼ 0001 ovarian cancers in the 1st degree p ¼ 0006 and pancreatic cancers p ¼ 0028 in gBRCAm carriers None of the patients in this cohort had a history of cancer The treatments administered are summarized in Table 2 Chemotherapy regimens and settings were comparable between gBRCA carriers and gBRCA noncarriers with the preferential use of a sequential regimen including anthra cyclines and taxanes Surgery was mostly conservative in almost twothirds of the cases and the indications for radiotherapy did not vary between the groups There was no significant difference in the prescription of endocrine therapy for patients with hormone receptorpositive tu mors between the two groups Similarly all HER2positive patients were administered trastuzumab Comparison of Prognosis and Longterm Survival of gBRCA Carriers vs Noncarriers OS and DFS are illustrated in Figure 1 and the results of the Cox regression models are presented in Tables 3 and 4 Twentyfour patients died during the study The OS median followup was 82 years IQR 080e176 OS was 893 704e964 in gBRCA carriers vs 992 95 CI 943e999 in noncarriers at 2 years 852 652e942 vs 930 865e965 at 5 years and 765 547e888 vs 852 757e912 at 10 years Figure 1A There was no difference in OS between the groups either before or after accounting for known prognostic factors including pathological stage clinical tumor and nodal stage and triplenegative breast cancer status univariate analysis carriers vs noncarriers HR 176 95 CI 073e425 p ¼ 021 multivariate analysis F Hego et al Clinical Oncology 37 2025 103658 3 Table 1 Patient characteristics and clinicopathological information All patients n149 BRCA noncarriers n121 BRCA carriers n28 pvalue Age at diagnosis 0603 Median IQR range 28 2230 28 2229 27 2330 Grade 0015 III 57 404 52 452 5 192 III 84 596 63 548 21 808 Missing 8 537 6 50 2 71 Clinical tumor stage 0321 T1 47 324 42 35 5 20 T2 80 552 64 533 16 64 T3 15 103 12 10 3 12 T4 3 21 2 17 1 4 Missing 4 27 1 08 3 107 Clinical nodal stage 0011 N0 103 705 90 75 13 50 N1 43 295 30 25 13 50 Missing 3 20 1 08 2 71 Ki67 018 20 77 786 63 759 14 933 20 21 214 20 241 1 67 Missing 51 342 38 314 13 464 Hormonalreceptor status 0011 Positive 80 537 71 587 9 321 Negative 69 463 50 413 19 679 HER2 status 104 Positive 48 322 48 397 0 0 Negative 101 678 73 603 28 100 Triplenegative breast cancer status a 104 No 96 644 87 719 9 321 Yes 53 356 34 281 19 679 Age at first periods NA20 20 15 5 0693 MedianMinMax 12 917 12 917 13 1017 Meanstandard deviation 125 16 125 16 126 16 Pregnancy 0639 No pregnancy 65 436 52 43 13 464 1 pregnancy 36 242 28 231 8 286 1 pregnancy 48 322 41 339 7 25 Age at 1st pregnancy 1 18 7 83 6 87 1 67 18 77 917 63 913 14 933 BMI NA6 6 3 3 0257 25 101 706 81 686 20 80 25 42 294 37 314 5 20 Type of contraception NA16 16 12 4 0575 No oral contraception 13 98 12 11 1 42 Estrogenprogestin pill 112 842 91 835 21 875 Progestinonly 8 6 6 55 2 83 Physical activity NA37 37 29 8 0565 Never or little 1 hourweek 78 696 63 685 15 75 Moderate to heavy 14 hoursweek 34 304 29 315 5 25 Family history of 1st degree breast cancer 0079 0 122 819 103 851 19 679 1 24 161 16 132 8 286 2 3 2 2 17 1 36 Family history of 2nd degree breast cancer 0006 0 98 658 85 702 13 464 1 34 228 26 215 8 286 2 10 67 4 33 6 214 3 7 47 6 5 1 36 HR ¼ 190 069e23 p ¼ 022 Table 3 Thirtyseven re currences six locoregional recurrences alone 27 metastatic recurrences alone four locoregional and metastatic re currences and seven second cancers five breast cancers and two ovarian cancers were reported during the study period The DFS median followup was 66 years IQR 080e165 DFS was 857 95 CI 663e944 in gBRCAm carriers vs 932 869e966 in gBRCA noncarriers at 2 years 701 490e838 versus 790 700e856 at 5 years and 561 344e731 versus 652 518e758 at 10 years Figure 1B There was no difference in DFS between groups either before or after adjusting for prognostic factors univariable analysis carriers vs noncarriers HR 149 95 CI 075e295 p ¼ 026 multivariable analysis HR 139 063e308 p ¼ 042 Clinical nodal status was the sole factor associated with poorer outcome multivariable analysis HR 261 116e583 Table 4 Discussion In this study we aimed to investigate outcomes of pa tients with gBRCA mutations and early onset of breast cancer 30 years compared with those of noncarriers and Table 1 continued All patients BRCA noncarriers BRCA carriers pvalue n¼149 n¼121 n¼28 Family history of early breast cancer 35 years 0001 0 137 919 116 959 21 75 1 11 74 4 33 7 25 2 1 07 1 08 0 0 Family history of 1st degree ovarian cancer 0006 0 146 98 121 100 25 893 1 3 2 0 0 3 107 Family history of prostate cancer 0728 0 135 906 110 909 25 893 1 14 94 11 91 3 107 Family history of melanoma 0028 0 139 933 115 95 24 857 1 8 54 6 5 2 71 Data are presented as median IQR range or n Patients with missing data were not included in the pvalue calculation ManneWhitney tests were used for continuous variables and Pearson c2 tests for categorical variables using data from patients with complete data a Defined as estrogenreceptor negative HER2negative and progesteronereceptor negative Table 2 Treatments received by gBRCA carriers N ¼ 28 and noncarriers N ¼ 121 All patients gBRCA noncarriers gBRCA carriers pvalue n¼149 n¼121 n¼28 Type of breast surgery NA 1 1 1 1 Partial 85 574 69 57 16 593 Total 58 392 48 397 10 37 Partial then total 5 34 4 33 1 37 Chemotherapy 1 No 8 54 7 58 1 36 Yes 141 946 114 942 27 964 Type of chemotherapy 0343 Neoadjuvant 69 489 58 509 11 407 Adjuvant 72 511 56 491 16 593 Chemotherapy protocol 0094 Anthracyclines 3 21 1 09 2 74 Anthracyclines and taxanes 138 979 113 991 25 926 Radiotherapy 0172 No 8 54 5 41 3 107 Yes 141 946 116 959 25 893 Hormone therapy NA1 1 1 0012 No 69 466 50 417 19 679 Yes 79 534 70 583 9 321 Trastuzumab 0001 No 102 685 74 612 28 100 Yes 47 315 47 388 0 0 Data are presented as n Pearson c2 tests were used for categorical variables performed on data from patients with complete data F Hego et al Clinical Oncology 37 2025 103658 5 Figure 1 A Overall survival by BRCA mutation status B Diseasefree survival by BRCA mutation status Table 3 Cox regression models of prognostic factors for overall survival Number of events number of patients Univariate analysis Multivariable analysis HR 95 CI pvalue HR 95 CI pvalue Mutation BRCA 021 022 BRCA noncarriers 17121 1 1 BRCA carriers 728 176 073425 19 069523 BMI MD6 082 25 17101 1 25 642 09 035227 Clinical tumor stage MD4 051 T1 647 1 T2 1380 157 060415 T3T4 418 201 057713 Clinical nodal stage MD3 0013 N0 12103 1 N1 1243 275 123613 Clinical tumor and nodal stage 016 077 T1 N0T1 N1a 647 1 1 T2T4 N0 757 115 039342 111 036338 T2T4 N1 1041 241 087664 113 024523 Grade MD8 088 077 III 1057 1 1 III 1384 094 041214 116 044306 Hormonalreceptor status 061 Positive 1480 1 Negative 1069 081 036182 HER2 status 062 Positive 948 1 Negative 15101 081 036186 Triplenegative breast cancer status 045 No 1796 1 Yes 753 071 029171 Ki67 MD51 044 Positive 1277 1 Negative 221 056 012249 a Only one patient T1N1 b Multivariable analysis was adjusted for mutation BRCA main independant variable clinical tumor and nodal stage grade and stratified on triplenegative breast cancer status Table 4 Cox regression models of prognostic factors for diseasefree survival Number of events number of patients Univariate analysis Multivariable analysis HR 95 CI pvalue HR 95 CI pvalue Mutation BRCA 025 042 BRCA noncarriers 30121 1 1 BRCA carriers 1428 149 075295 139 063308 BMI MD6 082 25 30101 1 25 1342 092 046185 Clinical tumor stage MD4 036 096 T1 1147 1 1 T2 2480 139 068286 095 042216 T3T4 718 198 077513 108 034345 Clinical nodal stage MD3 0002 002 N0 23103 1 1 N1 2043 267 145490 261 116583 Grade MD8 047 082 III 1857 1 1 III 2384 08 043148 092 044189 Hormonalreceptor status 028 Positive 2680 1 Negative 1869 071 038132 HER2 status 018 Positive 1648 1 Negative 28101 065 034121 Triplenegative breast cancer status 020 019 No 3096 1 1 Yes 1453 065 033128 056 024133 Ki67 MD51 015 Positive 2377 1 Negative 321 048 014149 Multivariable analysis was adjusted for mutation BRCA main independant variable clinical tumor stage clinical nodal stage grade and triplenegative breast cancer status found no clear evidence that gBRCAm significantly affects OS and DFS after adjusting for known prognostic factors In this large hospitalbased cohort of very young patients with breast cancer we did not observe a significant difference in OS or DFS between gBRCAm carriers and noncarriers Additionally the results remained consistent even after accounting for known prognostic factors In our cohort 19 of the patients were gBRCAm carriers in accordance with literature confirming the high incidence of these gene alterations in patients under 30 years of age 39 The biological characteristics of breast cancer in young women have been described with young age being associated with aggressive molecular features 10 Similarly aggressive histological subtypes and grades were prevalent in our population TBBC 33 and HER2positive tumors 33 and grade 3 tumors 60 These characteristics confirm the poorer prognosis of this group of young patients compared to that of the general population regardless of the mutational status 1112 Among the gBRCAm carriers 13 RHHER2tumors 23 triplenegative tumors and no HER2positive tumors were present with 80 of the tumors being grade 3 In our study cohort patients with BRCA1 mutations were more frequent than those with BRCA2 mutations 19 and nine respectively This was consistent with literature stating that triplenegative phenotype and the absence of HER2 overexpression are present even in younger women with a higher proportion of BRCA1 mutations and highgrade alterations 1314 Moreover 1719 triplenegative tumors were found in patients with BRCA1 mutations and 79 RHHER2tumors were found in patients with BRCA2 mutations All cases were detected after clinical manifestations palpable tumors as commonly reported in the literature 15 OS and invasive DFS at 5 years 909 and 772 respectively were also consistent with the literature 1617 While treatment was consistent in our cohort molecular biology has undergone major technical and scientific improvements with the availability of nextgeneration sequencing and the expansion of the panel of genes studied initially limited to BRCA1 and 2 However this limitation to BRCA1 and 2 in our study cohort did not seem to be an issue In 2020 Evans et al explored the benefits of using a larger gene panel in young patients In their study 379 patients 30 years of age were tested using a panel that included BRCA1 BRCA2 TP53 PALB2 CHEK2 ATM CDH1 PTEN RAD50 RAD51D and NBN The rates of BRCA1 BRCA2 and TP53 PVs were high in very early onset breast cancer approximately 35 however testing of additional breast cancerassociated genes provides limited benefit 18 None of the patients in this cohort had a history of cancer Moreover we found a significantly increased familial risk of breast cancer among seconddegree relatives and early breast cancer 35 years in cases of gBRCAm similar to that in ovarian and pancreatic cancers Although we were unable to demonstrate an excess risk of familial history of prostate cancer our data are consistent with the literature showing no excess risk of melanoma 19 Our data confirmed the increased risk of early breast cancer in patients with a family history of early breast cancer included in the current breast screening guidelines in contrast to recent French data 820 The incidence of secondary cancers was low with five contralateral breast cancers of which three were in patients with BRCA1 mutations and two ovarian cancers both in patients with BRCA1 mutations and diagnosed via surgical specimens from reducedrisk bilateral salpingooophorectomy This low number of secondary cancers may be explained by the short followup period Given the early onset of the first event 20 years of followup is required 21 However these patients have the opportunity to undergo riskreducing surgeries Twenty patients underwent breast reduction risk surgery while six underwent a reduction risk oophorectomy Our results were consistent with those of other studies on earlyonset breast cancer In a prospective study of 2733 patients aged 40 years Copson et al showed no difference in overall survival between mutated and nonmutated groups except for an OS advantage at 2 years in patients with a gBRCAm for patients with triplenegative tumors However this difference was not observed at 5 and 10 years 6 In contrast in a retrospective study Schmidt et al found poorer OS in patients with breast cancer aged 50 years who carried gBRCAm 7 Regardless of the highquality methodology of these different studies their discordant results could be because of the prospective or retrospective nature of the studies the period of inclusion the heterogeneity of the treatments received and the short duration of followup Finally a metaanalysis of 66 studies found no specific survival difference for gBRCA1 or gBRCA2 mutated breast cancer patients 5 Our study had several strengths First it focused on patients 30 years old who are often poorly represented in the literature including studies focusing on young andor mutated women 671121 Second the recruitment period ensured homogeneous treatment sequential chemotherapy protocol with anthracyclines and taxanes access to trastuzumab and endocrine therapy Third we included data on personal risk factors for breast cancer that were prospectively collected and rarely assessed in this population physical activity parity age at first pregnancy and contraception Finally the median followup of more than 6 years and over 8 years for death data is a major strength of this study In contrast the main limitations of this study were its retrospective design and the limited sample size which may have prevented the emergence of statistically significant differences despite the hazard ratio being 1 for carriers as compared to the noncarriers This suggests a higher risk of worse prognosis for carriers than noncarriers Furthermore our sample size was limited to statistically separate the gBRCA1m and gBRCA2m patients Conclusions In this cohort of very young patients with breast cancer 30 years old we highlighted the frequency of highgrade breast cancers mostly triple negative and diagnosed on clinical manifestations and associated with a pathogenic constitutional variant of BRCA 1 or 2 in nearly 20 of cases Our results do not support the impact of BRCA1 or BRCA2 germline mutations on outcomes after adjusting for known prognostic factors Finally understanding the factors of very early onset and the prognostic impact of germline BRCA mutations and other personal risk factors for breast cancer remains a major challenge for optimizing the therapeutic management and monitoring of these patients Informed consent statement As this study was not interventional no signed consent was requested however the nonobjection of patients to the use of their data was checked Author contribution Conceptualization A Mailliez Methodology MBarthoulot Validation A Mailliez F Hego M Barthoulot Formal analysis MBarthoulot InvestigationF Hego A Mailliez ResourcesF Hego A Mailliez Data curation A Mailliez F Hego Writingoriginal draft preparation MBarthoulot A Mailliez F Hego Writingreview and editing All coauthors Visualization A Mailliez F Hego Supervision A Mailliez Project administration A Mailliez All authors have read and agreed to the published version of the manuscript Institutional review board statement This study was conducted in accordance with the Declaration of Helsinki and French Regulations MR004 This study was approved by the Institutional Review Board of the Oscar Lambret Centre protocol code 2022012 May 242022 Data availability The dataset used and analyzed in the current study is available from the corresponding author upon reasonable request Funding This study received no external funding Conflict of interest The authors declare no conflict of interest Acknowledgments We are grateful to Valerie Delage and Ludivine Dhalluin for their assistance with the availability of medical records References 1 Cardoso F PaluchShimon S Senkus E Curigliano G Aapro MS André F et al 5th ESOESMO international consensus guidelines for advanced breast cancer ABC 5 Ann Oncol 2020311216231649 2 Rebbeck TR Mitra N Wan F Sinilnikova OM Healey S McGuffog L et al Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer JAMA 20153131313471361 3 Pujol P Barberis M Beer P Friedman E Piulats JM Capoluongo ED et al Clinical practice guidelines for BRCA1 and BRCA2 genetic testing Eur J Cancer 20211463047 4 Chen HL Zhou MQ Tian W Meng KX He HF Effect of Age on Breast Cancer Patient Prognoses A PopulationBased Study Using the SEER 18 Database PLoS One 20161110e0165409 5 van den Broek AJ Schmidt MK van t Veer LJ Tollenaar RAEM van Leeuwen FE Worse breast cancer prognosis of BRCA1 BRCA2 mutation carriers whats the evidence A systematic review with metaanalysis PLoS One 2015103 e0120189 6 Copson ER Maishman TC Tapper WJ Cutress RI Greville Heygate S Altman DG et al Germline BRCA mutation and outcome in youngonset breast cancer POSH a prospective cohort study Lancet Oncol 2018192169180 7 Schmidt MK van den Broek AJ Tollenaar RAEM Smit VTHBM Westenen PJ Brinkhuis M et al Breast Cancer Survival of BRCA1BRCA2 Mutation Carriers in a HospitalBased Cohort of Young Women cité 13 févr 2022 JNCI J Natl Cancer Inst Internet 20171098 Disponible sur httpacademicoupcomjnciarticledoi101093jncidjw3293064570Breast CancerSurvivalofBRCA1BRCA2Mutation 8 INCA Synthèse Femmes porteuses dune mutation de BRCA1 ou BRCA2Détection précoce du cancer du sein et des annexes et stratégies de réduction du risque 2017 9 Kast K Rhiem K Wappenschmidt B Hahnen E Hauke J Bluemcke B et al Prevalence of BRCA12 germline mutations in 21 401 families with breast and ovarian cancer J Med Genet 2016537465471 10 Azim HA Michiels S Bedard PL Singhal SK Criscitiello C Ignatiadis M et al Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling Clin Cancer Res 201218513411351 11 Copson E Eccles B Maishman T Gerty S Stanton L Cutress RI et al Prospective observational study of breast cancer treat ment outcomes for UK women aged 1840 years at diagnosis the POSH study J Natl Cancer Inst 201310513978988 12 Evans DGR Moran A Hartley R Dawson J Bulman B Knox F et al Longterm outcomes of breast cancer in women aged 30 years or younger based on family history pathology and BRCA1BRCA2TP53 status Br J Cancer 2010102710911098 13 Chappuis PO Nethercot V Foulkes WD Clinicopathological characteristics of BRCA1 and BRCA2related breast cancer Semin Surg Oncol 2000184287295 14 GuzmánArocho YD Rosenberg SM Garber JE Vardeh H Poorvu PD Ruddy KJ et al Clinicopathological features and BRCA1 and BRCA2 mutation status in a prospective cohort of young women with breast cancer Br J Cancer 20221262 302309 15 Ruddy KJ Gelber S Tamimi RM Schapira L Come SE Meyer ME et al Breast cancer presentation and diagnostic delays in young women Cancer 201412012025 16 Anders CK Johnson R Litton J Phillips M Bleyer A Breast cancer before age 40 years Semin Oncol 2009363237249 17 Miller KD FidlerBenaoudia M Keegan TH Hipp HS Jemal A Siegel RL Cancer statistics for adolescents and young adults 2020 CA Cancer J Clin nov 2020706443459 18 Evans DG van Veen EM Byers HJ Evans SJ Burghel GJ Woodward ER et al High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer J Med Genet 2022592115121 19 Li S Silvestri V Leslie G Rebbeck TR Neuhausen SL Hopper JL et al Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants J Clin Oncol 20224014 15291541 20 ImbertBouteille M Corsini C Picot MC Mizrahy L Akouete S Huguet H et al No Association of EarlyOnset Breast or Ovarian Cancer with EarlyOnset Cancer in Relatives in BRCA1 or BRCA2 Mutation Families Genes Basel 20211271100 21 Lambertini M Ceppi M Hamy AS Caron O Poorvu PD Carrasco E et al Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants NPJ Breast Cancer 20217116 1INTRODUÇÃO 2 OBJETIVO O câncer de mama é o tipo mais comum entre as mulheres globalmente principalmente em mulheres com mais de 50 anos 1 sendo raro em mulheres com menos de 30 anos representando apenas cerca de 05 dos casos As variantes patogênicas da linha germinativa dos genes BRCA1 e BRCA2 gBRCAm são responsáveis por cerca de 5 dos cânceres de mama 2 mas essa proporção aumenta para 6 20 entre mulheres com menos de 30 anos 3 A identificação precoce de portadores de gBRCAm é incentivada com estratégias específicas de triagem e prevenção como exames clínicos e de imagem anuais a partir dos 30 anos conforme recomendações francesas 8 Essa idade marca um ponto crítico em que o risco de câncer de mama em portadoras aumenta significativamente Comparar a sobrevida e características clínicas entre mulheres com e sem mutações BRCA diagnosticadas com câncer de mama antes dos 30 anos PROGNÓSTICO DO CÂNCER DE MAMA EM JOVENS PORTADORES DE MUTAÇÃO BRCA1BRCA2 UM ESTUDO DE COORTE RETROSPECTIVO EM HOSPITAL Autores F Hego M Barthoulot S Chretien C Pierard M Boulaire S Bécourt L Boulanger L Ceugnart AL Conoy F Oca A Mailliez 4 RESULTADOS Sobrevida global SG 5 anos 852 portadoras vs 930 não portadoras Sobrevida livre de doença SLD 5 anos 701 portadoras vs 790 não portadoras Sem diferença estatisticamente significativa entre os grupos após ajuste por fatores prognósticos Fatores de risco associados em portadoras Câncer de ovário em parentes de 1º grau Câncer de pâncreas Câncer de mama precoce em parentes 3 MATERIAL E MÉTODOS Tipo de estudo Coorte retrospectiva 2005 2019 Local Centro Oscar Lambret França População Mulheres 30 anos com câncer de mama invasivo e testadas para BRCA12 Análises estatísticas KaplanMeier SG e SLD e modelos de Cox multivariados Critérios de exclusãoHomens recidiva pré 2005 câncer metastático no diagnóstico 5 DISCUSSÃO O estudo não encontrando diferenças significativas na sobrevida global SG e sobrevida livre de progressão DFS após ajuste para fatores prognósticos conhecidos Na coorte analisada 19 das pacientes eram portadoras de gBRCAm taxa consistente com a literatura para essa faixa etária 3 9 Foram observadas características tumorais agressivas comuns em mulheres jovens com câncer de mama 10 como alto grau histológico 60 câncer de mama triplo negativo 33 e HER2positivo 33 o que confirma o pior prognóstico desse grupo independentemente do status de BRCA 11 12 7 REFERÊNCIAS 6 CONCLUSÕES Os resultados não dão suporte ao impacto das mutações germinativas BRCA1 ou BRCA2 nos resultados após o ajuste para fatores prognósticos conhecidos F Cardoso S PaluchShimon E Senkus G Curigliano MS Aapro F André et al 5ª Diretriz de consenso internacional ESOESMO para câncer de mama avançado ABC 5 Ann Oncol 31 12 2020 pp 1623 1649 TR Rebbeck N Mitra F Wan OM Sinilnikova S Healey L McGuffog e outros Associação do tipo e localização das mutações BRCA1 e BRCA2 com risco de câncer de mama e ovário JAMA 313 13 2015 pp P Pujol M Barberis P Beer E Friedman JM Piulats ED Capoluongo et al Diretrizes de prática clínica para testes genéticos BRCA1 e BRCA2 Eur J Cancer 146 2021 pp Synthèse Mulheres portadoras de uma mutação de BRCA1 ou BRCA2 Detecção precoce de câncer de câncer e anexos e estratégias de redução de risco 2017 K Kast K Rhiem B Wappenschmidt E Hahnen J Hauke B Bluemcke et al Prevalência de mutações germinativas BRCA12 em 21401 famílias com câncer de mama e ovário J Med Genet 53 7 2016 pp HA Azim S Michiels PL Bedard SK Singhal C Criscitiello M Ignatiadis et al Elucidando o prognóstico e a biologia do câncer de mama que surge em mulheres jovens usando o perfil de expressão gênica Clin Cancer Res 18 5 2012 pp 1341 1351 E Copson B Eccles T Maishman S Gerty L Stanton RI Cutress et al Estudo observacional prospectivo de resultados do tratamento do câncer de mama em mulheres do Reino Unido com idade entre 18 e 40 anos no momento do diagnóstico o estudo POSH J Natl Cancer Inst 105 13 2013 pp 978988 DGR Evans A Moran R Hartley J Dawson B Bulman F Knox e outros Resultados de longo prazo do câncer de mama em mulheres com 30 anos ou menos com base na história familiar patologia e status BRCA1BRCA2TP53 Br J Câncer 102 7 2010 pp 1091 1098 ER Copson TC Maishman WJ Tapper RI Cutress S GrevilleHeygate DG Altman et al Mutação da linha germinativa BRCA e desfecho no câncer de mama de início precoce POSH um estudo de coorte prospectivo Lancet Oncol 19 2 2018 pp 169180 Amostra 149 pacientes 121 não portadoras 28 portadoras de BRCA12 Frequência de BRCA 188 Subtipos tumorais Triplonegativo mais comum entre portadoras de BRCA 67 HER2 mais comum entre não portadoras Sobrevida global SG 5 anos 852 portadoras vs 930 não portadoras Os resultados confirmam achados anteriores Copson et al não observaram diferença de SG entre portadoras e não portadoras de gBRCAm 40 anos exceto por uma vantagem inicial em casos triplo negativos 6