SurvivorCHIP: Evaluation of clonal hematopoiesis in women treated for breast cancer

Background: Clonal hematopoiesis (CH) has been associated with reduced overall survival and is shown to be increased in patients with solid tumors after receiving chemotherapy and radiotherapy. However, the clinical implications of these observations have not been prospectively evaluated among different racial groups. This study was initiated in an urban cancer center to study CH rates before and after cancer therapy in a racially diverse population. Methods: Women aged $18 with newly diagnosed non-metastatic breast cancer provided written informed consent for this IRB approved study. Error-corrected DNA-sequencing was performed on 50ng gDNA isolated from blood prior to (pre-Tx), and following (post-Tx), chemotherapy(C), radiotherapy(R), and/or endocrine (E) therapy. Pathogenic or likely pathogenic variants were determined in regions recurrently mutated in CH. Results: 56 patients, median age 59.5y (29–82), provided both pre-Tx and post-Tx blood samples. Median BMI was 31.2 (range: 21.1–52.7) with 48 (85%) overweight (BMI$25) and 33 (59%) obese (BMI$30). 21 (38%) were active smokers. CH variants with an allele frequency (VAF) $2% were identified in 8 (14%) patients pre-Tx, most commonly DNMT3A (5 patients). For those with CH, median age was 64y (49–80) and 5 were active smokers. BMI was not statistically associated with pre-Tx CH in this cohort. 48 (86%) of the patients self-identified as African American and 7 (15%) had CH pre-Tx. Post-Tx, 10 patients had CH (18%), persistent from pre-Tx in 7. Of those with different CH classifications pre- and post-Tx, 1 had DNMT3A CH pre-Tx no longer detectable post-Tx (CRE), 2 had DNMT3A CH detectable at VAF $2% post-Tx (1 with CH undetected prior to RE Tx, 1 with the same DNMT3A variant at 1.2% VAF prior to CRE), and a 3rd had a ATRX variant increase from 1.5% to 2.1% VAF post-Tx (CRE). To investigate potential clinical implications of CH post-Tx, we utilized the clonal hematopoiesis risk score (CHRS) calculator which aims to predict risk of developing MDS and AML (Weeks et al, NEJM). Pre-Tx, 6 of the CH patients were classified as low risk, and 2 as intermediate risk. Patients developing CH post-Tx were all classified as low risk. Risk scores remained otherwise unchanged. At a median follow up of 2y, none of the patients in this study have been reported to develop MDS or AML. Conclusions: In this cohort of patients with newly diagnosed non-metastatic breast cancer, we did not find evidence to justify clinical screening/monitoring for CH before and after therapy. Research Sponsor: Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health; 1ZIAHL006163.