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Background: This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across KRAS subtypes and in different KRAS subtypes across cancers, and to identify potentially actionable targets and patients who received targeted treatment matched to their genomic profile (GP)., Materials and Methods: In this descriptive and single-center study, we included 188 patients with solid tumors harboring KRAS mutations in codon 12, 13, 61, 117, or 146, referred to the Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark from mid-2016 to 2020. Genomic co-alterations were detected with whole-exome sequencing, RNA sequencing, SNP array, and mRNA expression array on fresh biopsies. The study is part of the Copenhagen Prospective Personalized Oncology study (NCT02290522)., Results: The majority of patients had colorectal cancer (60.1%), non-small cell lung cancer (11.2%), or pancreatic cancer (10.6%). Most tumors were KRAS -mutated in codon 12 or 13 (93.7%) including G12D (27.1%), G12V (26.6%), G12C (11.7%), and G13D (11.2%). A total of 175 different co-alterations were found, most frequently pathogenic APC and TP53 mutations (55.9% and 46.4%, respectively) and high expression of CEACAM5 (73.4%). Different cancers and KRAS subtypes showed different patterns of co-alterations, and 157 tumors (83.5%) had potentially actionable targets with varying evidence of targetability (assessed using ESMO Scale for Clinical Actionability of molecular Targets). Of the 188 patients included in the study, 15 (7.4%) received treatment matched to their GP (e.g., immunotherapy and synthetic lethality drugs), of whom one had objective partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1., Conclusion: Performing extensive genomic analysis in patients with known KRAS -mutated solid tumors may contribute with information to the genomic landscape of cancers and identify targets for immunotherapy or synthetic lethality drugs, but currently appears to have overall limited clinical impact, as few patients received targeted therapy matched to their GP.

Background: Transcriptome analysis enables classification of breast tumors into molecular subtypes that correlate with prognosis and effect of therapy. We evaluated the clinical benefits of molecular subtyping compared to our current diagnostic practice., Materials and Methods: Molecular subtyping was performed on a consecutive and unselected series of 524 tumors from women with primary breast cancer (n = 508). Tumors were classified by the 256 gene expression signature (CIT) and compared to conventional immunohistochemistry (IHC) procedures., Results: More than 99% of tumors were eligible for molecular classification and final reports were available prior to the multidisciplinary conference. Using a prognostic standard mortality rate index (PSMRi) developed by the Danish Breast Cancer Group (DBCG) 39 patients were assigned with an intermediate risk and among these 16 (41%) were furthermore diagnosed by the multi-gene signature assigned with a luminal A tumor and consequently spared adjuvant chemotherapy. There was overall agreement between mRNA derived and IHC hormone receptor status, whereas IHC Ki67 protein proliferative index proved inaccurate, compared to the mRNA derived index. Forty-one patients with basal-like (basL) subtypes were screened for predisposing mutations regardless of clinical predisposition. Of those 17% carried pathogenic mutations., Conclusion: Transcriptome based subtyping of breast tumors evidently reduces the need for adjuvant chemotherapy and improves identification of women with predisposing mutations. The results imply that transcriptome profiling should become an integrated part of current breast cancer management.

Background: Transcriptome analysis enables classification of breast tumors into molecular subtypes. BRCA1/2 predisposed patients are more likely to suffer from a basal-like subtype and this group of patients displays a more distinct phenotype and genotype. Hence, in-depth characterization of this separate entity is needed., Material and Methods: Molecular subtyping was performed on a consecutive and unselected series of 1560 tumors from patients with primary breast cancer. Tumors were classified by the 256 gene expression signature (CIT) and associated with basic clinical characteristics and aggregated expression levels in the hallmark gene sets., Results: Of the 1560 samples, 168 were classified basal-like and 120 patients were screened for BRCA1/2 mutations, resulting in 19 BRCA1/2 carriers, 95 non-carriers and six patients carried variants of unknown significance. The BRCA1/2 carriers were significantly younger and there were no carriers above 60 years of age. The tumors showed a loss in DNA-repair profile, as well as an upregulation in proliferative cancer signaling pathways. A robust molecular signature for identification of the BRCA1/2 - carriers was infeasible in the current cohort. Patients with a basal like breast cancer had the lowest median age and the largest median tumor size. They were almost exclusively diagnosed in disease stage III., Conclusions: Basal-like subtype is indeed a separate entity compared with other molecular breast cancer subtypes and the clinical course for this patient group should reflect the aggressiveness of this cancer. Taken together, patients being diagnosed with a basal-like breast cancer are in the youngest segment of breast cancer patients and are mainly diagnosed in stage III disease.

A national study of BRCA1 and BRCA2 mutations in Danish HBOC (Hereditary Breast Ovarian Cancer) families revealed a total number of 322 mutation positive families, 206 (64%) BRCA1 and 116 (36%) BRCA2 positive families from a population of 5.5 million inhabitants. Seven hundred and twenty six mutation positive individuals were identified: 402 female BRCA1 carriers, 79 male BRCA1 carriers, 213 female BRCA2 carriers, and 32 male BRCA2 carriers by April 2006. Most of the mutations were frame shift or nonsense mutations, while large genomic rearrangements were rare. Most mutations were only identified in one family. A few mutations were detected repeatedly. In BRCA1 the most common mutations were: 2594delC in 32 families (16%), 3438G>T in 19 families (9%), 5382insC in 16 families (8%), 3829delT in 11 families (5%). In BRCA2 the most common mutations were: 6601delA in 13 families (11%), 1538del4 in 12 families (10%), 6714del4 in 10 families (9%). There was a tendency towards a higher frequency of BRCA2 mutations in West Denmark compared to East Denmark. The frequencies of specific BRCA1 and BRCA2 mutations were slightly different in the two regions. The mutations occurring in West Denmark have also been observed in other Scandinavian countries whereas the mutations occurring in East Denmark were more often reported from other European countries and the Baltic countries. The pattern of mutation distributions are comparable with observations from other Scandinavian and European studies and indicate that the Danish BRCA1 and BRCA2 mutations are a mixture of Scandinavian mutations and other European mutations including two of the Ashkenazi mutations. Even though a tendency towards founder mutations was observed most mutations were only detected once. Based on these observations we recommend that the mutation screening strategy of the BRCA1 and BRCA2 genes in Danish HBOC families comprises full screening of both genes including analysis for large genomic rearrangements.