Pujol Pascal, Yauy Kevin, Coffy Amandine, Duforet-Frebourg Nicolas, Gabteni Sana, Daurès Jean-Pierre, Penault Llorca Frédérique, Thomas Frédéric, Hughes Kevin, Turnbull Clare, Galibert Virginie, Rideau Chloé, Corsini Carole, Collet Laetitia, You Benoit, Geneviève David, Philippe Nicolas
Department of Cancer Genetics, CHU Montpellier, Université de Montpellier, 34000 Montpellier, France.
CREEC, UMR IRD 224-CNRS 5290 Université Montpellier, 34000 Montpellier, France.
Cancers (Basel). 2022 Jul 4;14(13):3266. doi: 10.3390/cancers14133266.
Poly(ADP-ribose) polymerase 1 inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA) in both the metastatic and adjuvant setting. Therefore, we need to reassess the frequency of gBRCA1 and gBRCA2 in order to redefine the criteria for women and tumor phenotype that should be tested.
We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with breast cancer and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected breast cancer patients with gBRCA.
We performed a meta-analysis of studies of unselected breast cancer that analyzed the relative contribution of gBRCA1 versus gBRCA2 among unselected breast cancer cases in gBRCA carriers. We then performed a meta-analysis of gBRCA carriage in unaffected individuals from genome-wide population studies, the gnomAD databank, and case-control studies.
The gene was involved in 54% of breast cancer cases in unselected patients with gBRCA (n = 108,699) and 60% of unaffected individuals (n = 238,973) as compared with 38% of the largest gBRCA family cohort (n = 29,700). The meta-analysis showed that 1.66% (95% CI 1.08-2.54) and 1.71% (95% CI 1.33-2.2) of unselected breast cancer patients carried gBRCA1 and gBRCA2, respectively. In a population of unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA. Carriage of a gBRCA was 2.5% for patients with ER+ tumors (95% CI 1.5-4.1) and 5.7% (95% CI 5.1-6.2) for those with ER- tumors. Overall, 58% of breast tumors occurring in women carrying a gBRCA were ER+ (n = 86,870).
This meta-analysis showed that gBRCA2 carriage is predominant in unselected breast cancer patients and unaffected individuals. ER+ tumors among women with gBRCA-related breast cancer are predominant and have been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA breast cancer in most clinical trials, breast cancer should be considered, regardless of ER status, for screening for therapeutic purposes.
聚（ADP - 核糖）聚合酶1抑制剂（PARPi）药物可改善携带种系BRCA1或BRCA2致病或可能致病变异（gBRCA）的乳腺癌患者在转移和辅助治疗环境中的无进展生存期。因此，我们需要重新评估gBRCA1和gBRCA2的频率，以便重新定义应接受检测的女性和肿瘤表型的标准。
我们研究了gBRCA1和gBRCA2在未选择的乳腺癌女性人群和未受影响个体中的相对分布。我们还分析了未选择的携带gBRCA的乳腺癌患者中雌激素受体（ER）阳性（ER +）肿瘤的比例。
我们对未选择的乳腺癌研究进行了荟萃分析，分析了gBRCA携带者中未选择的乳腺癌病例中gBRCA1与gBRCA2的相对贡献。然后，我们对来自全基因组人群研究、gnomAD数据库和病例对照研究的未受影响个体中的gBRCA携带情况进行了荟萃分析。
在未选择的携带gBRCA的患者（n = 108,699）中，54%的乳腺癌病例涉及该基因，在未受影响个体（n = 238,973）中为60%，而在最大的gBRCA家族队列（n = 29,700）中为38%。荟萃分析显示，未选择的乳腺癌患者中分别有1.66%（95%CI 1.08 - 2.54）和1.71%（95%CI 1.33 - 2.2）携带gBRCA1和gBRCA2。在未受影响个体人群中，gBRCA1和gBRCA2杂合子频率估计分别为1/434和1/288。在研究人群中，近0.5%的未受影响个体携带gBRCA。ER +肿瘤患者携带gBRCA的比例为2.5%（95%CI 1.5 - 4.1），ER -肿瘤患者为5.7%（95%CI 5.1 - 6.2）。总体而言，携带gBRCA的女性发生的乳腺癌中58%为ER +（n = 86,870）。
这项荟萃分析表明，在未选择的乳腺癌患者和未受影响个体中，gBRCA2携带占主导地位。携带gBRCA相关乳腺癌的女性中ER +肿瘤占主导地位且一直被低估。由于在大多数临床试验中PARPi药物可改善ER + gBRCA乳腺癌的无进展生存期，因此无论ER状态如何，出于治疗目的筛查乳腺癌都应被考虑。
