A 59-year-old man presented with a 3-week history of fatigue, light-headedness, and bifrontal headache. Two weeks earlier he had had watery diarrhea, including one episode of hematochezia, for 5 days.
Abstract Background: Previous studies have demonstrated poorer survival of Black women with breast cancer. We assessed whether race/ethnicity was associated with disease-free (DFS) and overall survival (OS) among women with breast cancer enrolled in clinical trials for early-stage breast cancer according to tumor subtype, age, and body mass index (BMI). Methods: 10,011 women enrolled in one of four adjuvant chemotherapy trials: CALGB 9741, CALGB 49907, CALGB 40101, or NCCTG N9831. 9918 participants had available DFS and/or OS data and were included in the analysis. Cox models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between race/ethnicity and DFS and OS. We compared Non-Hispanic (NH) Black (n=871), Hispanic (n=436), and other race participants (n=283) to NH Whites (n=7889). We assessed associations within strata of age group (<50, 50-<65, or ≥65), tumor subtype (hormone receptor (HR)+/HER2-, HR-/HER2+, or HR-/HER2-), and BMI (<25, 25-<30, or ≥30). Results: In multivariable-adjusted models, NH Black patients under 50 years of age had worse DFS compared to NH White patients (HR: 1.34, 95% CI: 1.10-1.62) and worse OS (HR: 1.64, 95% CI: 1.30-2.07). The differences in DFS and OS persisted in patients ages 50 to <65, though there were no significant differences in DFS or OS between NH Black and NH White patients ages ≥65. Among Hispanic and NH White participants, younger age at diagnosis was associated with greater DFS compared with older age overall while this was not true for NH Black patients. Among patients with HR+/HER2- tumors, NH Black patients when compared to NH White patients had worse DFS (HR 1.33, 95% CI: 1.04-1.70) but there was not a significant difference in OS (HR 1.35, 95% CI: 1.00-1.83). DFS and OS for other tumor subtypes did not significantly differ by race. Among patients with BMI <25, NH Black patients had significantly worse DFS (HR: 1.70, 95% CI: 1.25-2.30) and OS (HR:1.76, 95% CI:1.20-2.58) compared to NH White patients. There was no difference in survival between different race/ethnicity groups among individuals with BMI ≥25. Conclusions: Our results identified subgroups that may contribute to the observed disparities in survival between NH Black and NH White women with early-stage breast cancer. The greatest disparities are among individuals <50 years of age, those with HR+/HER2-, and those with BMI <25. These differences exist even within clinical trial populations with similar initial therapy, suggesting that disparities may be influenced by inequities in survivorship care and long-term treatment, such as endocrine therapy adherence and persistence, and/or differences in tumor or host biology. Support: U10CA180821 and U10CA180882; ClinicalTrials.gov Identifiers: NCT00003088, NCT00005970, NCT00024102, NCT00041119; https://acknowledgments.alliancefound.org Citation Format: Marla Lipsyc-Sharf, Karla V. Ballman, Jordan D. Campbell, Hyman B. Muss, Edith A. Perez, Lawrence N. Shulman, Lisa A. Carey, Ann H. Partridge, Erica T. Warner. Role of age, BMI, and tumor subtype in racial/ethnic disparities in breast cancer survival: A pooled analysis of four Alliance adjuvant clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 494.
PURPOSE Erb-B2 receptor tyrosine kinase 2 ( ERBB2)–positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. METHODS From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. RESULTS Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples. CONCLUSION ERBB2-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.
PURPOSE Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited. PATIENTS AND METHODS We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ≥0.005. RESULTS CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ≥0.005 (OR, 3.45; P = .002). Five TP53- mutant CH with VAF ≥0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC. CONCLUSION CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53 -mutant CH with VAF ≥0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.
<div>AbstractPurpose:<p>We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer.</p>Experimental Design:<p>We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (<i>n</i> = 17) and ≥10-year (<i>n</i> = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I–IV patients.</p>Results:<p>In the extremes-of-survivorship cohort, significant co-occurrence of <i>KRAS</i> hotspot mutations and <i>TP53</i> alterations was observed in ≤2-year survivors (<i>P</i> < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic <i>Ras/B-raf</i> (i.e., either <i>KRAS, NRAS</i>, or <i>BRAF</i>) and <i>TP53</i> alteration generated three prognostic clusters: (i) <i>TP53</i>-altered alone (median OS, 132 months); (ii) <i>Ras/B-raf</i>–altered alone (65 months) or <i>Ras/B-raf</i>- and <i>TP53</i> pan-wild-type (60 months); and (iii) coaltered <i>Ras/B-raf</i>–<i>TP53</i> (40 months; <i>P</i> < 0.0001). Coaltered <i>Ras/B-raf</i>–<i>TP53</i> was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91–3.21; <i>P</i> < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I–IV patients. Coaltered <i>Ras/B-raf</i>–<i>TP53</i> was associated with worse OS in patients with liver (<i>n</i> = 490) and lung (<i>n</i> = 172) but not peritoneal surface (<i>n</i> = 149) metastases. Moreover, coaltered <i>Ras/B-raf</i>–<i>TP53</i> tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options.</p>Conclusions:<p>Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered <i>Ras/B-raf</i>–<i>TP53</i> and its association with distinct patterns of colorectal cancer metastasis.</p></div>
