Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.
PurposeTriple negative breast cancer (TNBC) patients frequently receive neoadjuvant chemotherapy (NAC). Only 50% will achieve pathological complete response (pCR). In this retrospective study, we evaluated TNBC outcomes with NAC vs. AC.MethodsPatients with stages II and III TNBC treated with NAC or AC between 2010 and 2013 were identified from the National Cancer Database. Baseline characteristics were compared with χ2 and two sample t tests. Kaplan-Meier survival analyses were computed in patients treated with NAC or AC, and log-rank tests used to examine differences. Unadjusted analyses of trends in proportions over time were performed using Cochran–Armitage tests. Log-binomial models were applied to estimate relative risks of non-pCR following NAC.ResultsOf 19,151 patients, 5,621 (29.4%) received NAC, 13,530 (70.6%) received AC. NAC treated patients had worse OS compared to AC treated patients (73.4% vs. 76.8%; p<0.0001). pCR rate following NAC was 47.4%, and was associated with improved 5 year OS compared to non-pCR (86.2% vs. 62.3%; p<0.0001). In patients who received NAC, age, black race, clinical stage, diagnosis year, and Charlson-Deyo comorbidity score predicted non-pCR status. Use of NAC increased over the study period from 2010 to 2013 (27.8% - 31.2%; p = 0.0002).ConclusionsNAC may be inferior to AC in TNBC, likely related to the high frequency of non-pCR following NAC. It is unclear if removing the primary tumor prior to chemotherapy will have a beneficial biologic impact on therapeutic efficacy. These data should be considered hypothesis-generating as it is possible that the findings are due to selection bias, as physicians may use NAC for TNBC patients with more advanced local disease. Although, NAC still has a role in TNBC, developing biomarkers to identify patients likely to achieve pCR and benefit from NAC is an urgent need.
BackgroundThymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774).MethodsPatients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was > 10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3–5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels.ResultsDespite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% - 96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% - 100%) and 84% (95% CI 69.6% -98.4%), respectively. The κ-statistic was 0.76 (p < 0.001) between TK1 and Ki-67, indicating substantial agreement.ConclusionsSerum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation.Trial registrationClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0913-7) contains supplementary material, which is available to authorized users.
Macrophage metalloelastase or MMP-12 appears to exacerbate atherosclerosis, emphysema, aortic aneurysm, rheumatoid arthritis, and inflammatory bowel disease. An inactivating E219A mutation, validated by crystallography and NMR spectra, prevents autolysis of MMP-12 and allowed us to determine its NMR structure without an inhibitor. The structural ensemble of the catalytic domain without inhibitor is based on 2813 NOEs and has an average RMSD to the mean of 0.25 Å for the backbone and 0.61 Å for all heavy atoms for residues Trp109 -Gly263. Compared to crystal structures of MMP-12, helix B (hB) at the active site is unexpectedly more deeply recessed under the betasheet. This opens a pocket between hB and β-strand sIV in the active site cleft. Both hB and an internal cavity are shifted toward β-strands sI and sIII and hA on the back side of the protease. About 25 internal NOE contacts distinguish the inhibitor-free solution structure and indicate hB's greater depth and proximity to the sheet and hA. Line broadening and multiplicity of amide proton NMR peaks from hB are consistent with hB undergoing slow conformational exchange among subtly different environments. Inhibitor binding-induced perturbations of NMR spectra of MMP-1 and -3 map to similar locations across MMP-12 and encompassing its internal conformational adjustments. Evolutionary trace analysis suggests a functionally important network of residues that encompasses most of the locations that adjust in conformation, including 18 residues with NOE contacts unique to inhibitor-free MMP-12. The conformational change, sequence analysis, and inhibitor perturbations of NMR spectra agree in the network they identify between structural scaffold and active site of MMPs.
Purpose: Patients with triple negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin, and to identify molecular alterations and/or immune gene signatures predicting pCR.Experimental Design: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole exome sequencing (WES) and immune pro ling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular pro les.Results: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-signi cant trend towards higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80, versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR.Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor in ammation signature, in ammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteosome were upregulated in pre-treatment samples from patients who achieved pCR.Conclusions: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune pro ling differentiated patients with and without pCR.
Purpose Our purpose was to describe the risk of radiation-induced brachial plexopathy (RIBP) in patients with breast cancer who received comprehensive adjuvant radiation therapy (RT). Methods and Materials Records for 498 patients who received comprehensive adjuvant RT (treatment of any residual breast tissue, the underlying chest wall, and regional nodes) between 2004 and 2012 were retrospectively reviewed. All patients were treated with conventional 3 to 5 field technique (CRT) until 2008, after which intensity modulated RT (IMRT) was introduced. RIBP events were determined by reviewing follow-up documentation from oncologic care providers. Patients with RIBP were matched (1:2) with a control group of patients who received CRT and a group of patients who received IMRT. Dosimetric analyses were performed in these patients to determine whether there were differences in ipsilateral brachial plexus dose distribution between RIBP and control groups. Results Median study follow-up was 88 months for the overall cohort and 92 months for the IMRT cohort. RIBP occurred in 4 CRT patients (1.6%) and 1 IMRT patient (0.4%) ( P = .20). All patients with RIBP in the CRT cohort received a posterior axillary boost. Maximum dose to the brachial plexus in RIBP, CRT control, and IMRT control patients had median values of 56.0 Gy (range, 49.7-65.1), 54.8 Gy (47.4-60.5), and 54.8 Gy (54.2-57.3), respectively. Conclusions RIBP remains a rare complication of comprehensive adjuvant breast radiation and no clear dosimetric predictors for RIBP were identified in this study. The IMRT technique does not appear to adversely affect the development of this late toxicity.
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