Abstract PO1-08-06: Clinical-molecular correlation in breast cancer with pathogenic variants in CHEK2. Is there a relationship with HER2+ breast cancer?
Authors: Pérez-Rodríguez Natalia , Prieto-Morin Carol , Maeso Maria del Carmen , Pérez-Mendez Lina 
Published: May 2024

Abstract
Background: The CHEK2 gene codes for checkpoint protein Kinase 2 (CHK2), an effector in the ATM-CHK2-p53 DNA damage repair pathway in double-stranded DNA breaks. Initially, germline pathogenic variants were associated with moderate risk for breast carcinoma, but later studies linked alterations in the gene to other types of cancer. The aim of our study was to establish a clinical-molecular correlation of profiles of patients carrying pathogenic variants and variants of uncertain significance (VUS) in CHEK2 with a diagnosis of breast carcinoma, in patients treated in our hospital. And to describe whether the pathogenic variant c.1100del present different clinical or immunohistochemical characteristics than the rest, also considering the particularity of being an island population. Methodology: We have collected data from genetic studies performed in patients from our hospital, covering a population of 580,000 inhabitants, in Santa Cruz de Tenerife ( Canary Islands, Spain), between 2017 and 2023.Out of 952 patients with suspected hereditary cancer, 81 had CHEK2 mutations. In patients with CHEK2 mutations and breast cancer we established three groups for clinical molecular analysis: 1) pathogenic variant c.1100del, 2) other pathogenic variants and 3) VUS, to be correlated with age, histology, ER, PR, Ki, grade (G), HER2, second tumour or recurrence, subtype, HER2 low, aggressive clinic, neuropathy, haematological and digestive toxicity. The germline genetic study performed covered 77 genes related to hereditary cancer using the SureSelect HS library preparation kit (Agilent Technologies). The classification of the variants identified was performed according to the American College of Medical Genetics (ACMG) criteria. Results: In the 952 genetic studies performed, 8.5% of cases had CHEK2 mutations, 2.62% were related to breast carcinoma (N=26) of which 54% had the pathogenic variant “c.1100del”, 16% “other” pathogenic variants and 30% VUS. The mean age at diagnosis was 42 years, being lower than 38 years in pathogenic variants other than c.1100del. Histologically, infiltrating ductal carcinoma (85%) and mucinous carcinomas (12%), ER+ (93%), PR+ (77%), HER 2+ (31%), HER2 low (44%), G2-3 (84%) and Ki &gt;15% (70%) were predominant. Second diagnoses were tumour or recurrence in 40%, being higher in the group of pathogenic variants other than c.1100del (50%), and showing aggressive clinical course in 26%. The predominant subtype was luminal B (50%), HER2+ (31%), luminal A (12 %) and triple negative (7%), although in the cluster analysis patients with pathogenic variant c.1100del HER2+ were higher (38%) and luminal B (38%), while in pathogenic variants other than c.1100del and VUS the luminal subtype was predominant (75%). Chemotherapy toxicity: neuropathy (35%), haematological and digestive toxicity (50%). Conclusion: Our results are consistent with other reported series, being related with all breast carcinoma subtypes, mainly luminal B and HER2+ and with triple negative at a lesser extend. Considering HER2 low patients were about 75% of patients with CHEK2 mutations, a molecular mechanism that correlates a truncating mutation in CHK2 and HER2 overexpression can be hypothesized. In the cluster analysis, HER2+ (38%), and luminal B (38%) subtypes predominate in patients with pathogenic variant c.1100del, while in pathogenic variants other than c.1100del and VUS the luminal B subtype predominates (75%), as well as recurrence or second tumours in 50% of cases. On the other hand, considering that this is an island population, the possible effect of geographical isolation and the resulting inbreeding in the past, these facts do not seem to elicit differences comparing to the rest of the continental population, although the increase in pathogenic variants in CHEK2 were observed in patients from the small island of La Gomera. The relationship between CHEK2 and HER2 in breast cancer is an area of active research.
Relative frequency in groups of CHEK2 variants Relative frequency in CHEK2 “ pathogenic variants c.1100 del (53%)”, “other”pathogenic variants no c.1100 del (15 %)" and VUS (30%).
Relative frequency of breast cancer subtypes according to CHEK2 variants. HER2+: 30,8%. Luminal A: 11,5% . Luminal B: 50%. Triple negative: 7,7% .
Histology, ER, PR, Ki, HER2 and HER2 low Histology , infiltrating ductal carcinoma (84%), ER+ (92%), PR (77%), Ki &gt;15% (70%), HER2+ (31%), HER2 low (45%)
Citation Format: Natalia Pérez-Rodríguez, Carol Prieto-Morin, Maria del Carmen Maeso, Lina Pérez-Mendez. Clinical-molecular correlation in breast cancer with pathogenic variants in CHEK2. Is there a relationship with HER2+ breast cancer? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-06.