Clinical Outcome of Leiomyosarcomas With Somatic Alteration in Homologous Recombination Pathway Genes

Abstract

PURPOSE To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS). PATIENTS AND METHODS Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score. RESULTS Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; P = .035). Non- BRCA homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; P = .004) compared with BRCA-altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- BRCA homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- BRCA homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; P < .001). High HRD score was not associated with a different PFS or OS. CONCLUSION Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- BRCA gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes.

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

“…The HR deficiency status can be assessed by checking the percentage of genomic regions with loss of heterozygosity (LOH) using single nucleotide polymorphism (SNP) sequencing or by calculation of the Genomic Instability Score (GIS) via coalescing three parameters: LOH, large scale transitions (LSTs) and telomeric allelic imbalance (TAI). Other assays such as the FDA-approved MSK-IMPACT, which provides integrated mutation profiling of actionable cancer targets developed by Memorial Sloan Kettering’s Department of Pathology, also cover detection of somatic variants in DDR genes and allow evaluation of experimental HR deficiency scores ( 63 , 64 ). Recently, HRDetect, a new computational method dedicated to measuring HR deficiency based on whole-genome sequencing (WGS) data, is gaining momentum as a predictor of PARPi response.…”

Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review

“…The major biallelic inactivation of BRCA1 and/or BRCA2 in uLMS, which is one of the most proficient biomarkers for the response of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, is somatic homozygous deletion of BRCA2 , although germline pathogenic or likely pathogenic mutations, along with loss of heterozygosity (LOH), are major causes of biallelic inactivation of BRCA1/2 in other gynecologic malignancies, including ovarian cancer [ 49 ]. To date, the association between somatic BRCA1/2 variation in uLMS and ethnic-specificity has not been reported, but the prognosis of uLMS with loss of DNA repair-related genes was worse than that of uLMS without alterations in these genes [ 50 ].…”

“…Homologous recombination deficiency (HRD), including the pathogenic mutation in BRCA2 , was frequently observed, and BRCA2 deletion was observed in 50% (hemizygous deletion 40%, homozygous deletion 10%) of cases in uLMS [ 51 ]. Moreover, mutations in the BRCA2 gene were observed more frequently in uLMS than in nuLMS (approximately 10% vs. 1%) [ 50 , 52 ]. In a study where a cancer genome profile test was conducted on 80 cases of uLMS, Hensley et al reported that homozygous deletions and truncating mutations in BRCA2 were observed in 5% and 2.5% of cases, respectively [ 32 ].…”

“…In a study where a cancer genome profile test was conducted on 80 cases of uLMS, Hensley et al reported that homozygous deletions and truncating mutations in BRCA2 were observed in 5% and 2.5% of cases, respectively [ 32 ]. The frequency of BRCA gene mutations in uLMS reported to date ranges from 7.5% to 10%, and abnormalities in the homologous recombination repair (HRR)-related gene are reported to be approximately 18% overall [ 50 ].…”

Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets

“…Therapeutically targetable somatic alterations were labeled using levels of clinical actionability defined in OncoKB, which range from level 1, FDA-recognized biomarkers of response to FDA-approved drugs, to level 4, biomarkers of hypothetical relevance based on compelling preclinical biological evidence. Analyses of alterations in oncogenic signaling pathways were performed using the set of pathway definitions previously curated by our group, which we expanded to include the DDR and epigenetic modifier pathways using additional templates curated from literature subtypes (24,(51)(52)(53).…”