We previously demonstrated the clinical significance of circulating tumor DNA (ctDNA) in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy (NAC). Here, we compared its ...predictive and prognostic value with cell-free DNA (cfDNA) concentration measured in the same samples from the same patients.
145 patients with hormone receptor (HR)-positive/HER2-negative and 138 triple-negative breast cancer (TNBC) with ctDNA data from a previous study were included in the analysis. Associations of serial cfDNA concentration with residual cancer burden (RCB) and distant recurrence-free survival (DRFS) were examined.
In TNBC, we observed a modest negative correlation between cfDNA concentration 3 weeks after treatment initiation and RCB, but none of the other timepoints showed significant correlation. In contrast, ctDNA was significantly positively correlated with RCB at all timepoints (all R > 0.3 and P < 0.05). In the HR-positive/HER2-negative group, cfDNA concentration did not associate with response to NAC, but survival analysis showed that high cfDNA shedders at pretreatment had a significantly worse DRFS than low shedders (hazard ratio, 2.12; P = 0.037). In TNBC, the difference in survival between high versus low cfDNA shedders at all timepoints was not statistically significant. In contrast, as previously reported, ctDNA at all timepoints was significantly correlated with DRFS in both subtypes.
In TNBC, cfDNA concentrations during therapy were not strongly correlated with response or prognosis. In the HR-positive/HER2-negative group, pretreatment cfDNA concentration was prognostic for DRFS. Overall, the predictive and prognostic value of cfDNA concentration was more limited than that of ctDNA.
BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is ...one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57–1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36–0.95); no dose–response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HR
low versus never
= 0.93, 95%CI = 0.60–1.43; HR
medium versus never
= 0.81, 95%CI = 0.51–1.29; HR
high versus never
= 0.78, 95%CI = 0.48–1.29;
p
trend overall
= 0.272;
p
trend active women
= 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HR
medium versus low
= 0.60, 95%CI = 0.38–0.96; HR
high versus low
= 0.58, 95%CI = 0.35–0.94;
p
trend
= 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44–0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers.
Microarray analysis has been shown to improve risk stratification of breast cancer. Breast tumors analyzed by hierarchical clustering of expression patterns of "intrinsic" genes have been reported to ...subdivide into at least four molecular subtypes that are associated with distinct patient outcomes. Using a supervised method, a 70-gene expression profile has been identified that predicts the later appearance or absence of clinical metastasis in young breast cancer patients. Here, we show that distant metastases display both the same molecular breast cancer subtype as well as the 70-gene prognosis signature as their primary tumors. Our results suggest that the capacity to metastasize is an inherent feature of most breast cancers. Furthermore, our data imply that poor prognosis breast carcinomas classified either by the intrinsic gene set or the 70 prognosis genes represent distinct disease entities that seem sustained throughout the metastatic process.
Cellular senescence is a tumor suppressive mechanism that can paradoxically contribute to aging pathologies. Despite evidence of immune clearance in mouse models, it is not known how senescent cells ...(SnCs) persist and accumulate with age or in tumors in individuals. Here, we identify cooperative mechanisms that orchestrate the immunoevasion and persistence of normal and cancer human SnCs through extracellular targeting of natural killer receptor signaling. Damaged SnCs avoid immune recognition through MMPs-dependent shedding of NKG2D-ligands reinforced via paracrine suppression of NKG2D receptor-mediated immunosurveillance. These coordinated immunoediting processes are evident in residual, drug-resistant tumors from cohorts of >700 prostate and breast cancer patients treated with senescence-inducing genotoxic chemotherapies. Unlike in mice, these reversible senescence-subversion mechanisms are independent of p53/p16 and exacerbated in oncogenic RAS-induced senescence. Critically, the p16INK4A tumor suppressor can disengage the senescence growth arrest from the damage-associated immune senescence program, which is manifest in benign nevi lesions where indolent SnCs accumulate over time and preserve a non-pro-inflammatory tissue microenvironment maintaining NKG2D-mediated immunosurveillance. Our study shows how subpopulations of SnCs elude immunosurveillance, and reveals secretome-targeted therapeutic strategies to selectively eliminate -and restore the clearance of- the detrimental SnCs that actively persist after chemotherapy and accumulate at sites of aging pathologies.
Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 ...neoadjuvant platform trial.
To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents.
Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019.
Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide.
Pathologic complete response and 3-year EFS and DRFS.
Of the 950 participants (median range age, 49 23-77 years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS.
The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study.
ClinicalTrials.gov Identifier: NCT01042379.
The term breast cancer covers many different conditions, whose clinical course ranges from indolent to aggressive. However, current practice in breast cancer prevention and care, and in breast cancer ...epidemiology, does not take into account the heterogeneity of the disease. A comprehensive understanding of the etiology and progression of different breast cancer subtypes would enable a more patient-centered approach to breast health care: assessing an individual’s risk of getting specific subtypes of the disease, providing risk-based screening and prevention recommendations, and, for those diagnosed with the disease, tailored treatment options based on risk and timing of progression and mortality. The Athena Breast Health Network is an initiative of the five University of California medical and cancer centers to prototype this approach and to enable the development of a rapid learning system—connecting risk and outcome information from a heterogeneous patient population in real time and using new knowledge from research to continuously improve the quality of care. The Network is based on integrating clinical and research processes to create a comprehensive approach to accelerating patient-centered breast health care. Since its inception in 2009, the Network has developed a multi-site, transdisciplinary collaboration that enables the learning system. The five-campus collaboration has implemented a shared informatics platform, standardized electronic patient intake questionnaires, and common biospecimen protocols, as well as new clinical programs and multi-center research projects. The Athena Breast Health Network can serve as a model of a rapid learning system that integrates epidemiologic, behavioral, and clinical research with clinical care improvements.
Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a ...practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAF
tumours, we found mechanisms of intrinsic resistance to BRAF
-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAF
patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.
The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical ...outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL.
Expression data were collected before treatment (T1), 24-96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 - T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software.
When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 - T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS - T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS.
Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies.
ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002.
It has been debated for decades how cancer cells acquire metastatic capability. It is unclear whether metastases are derived from distinct subpopulations of tumor cells within the primary site with ...higher metastatic potential, or whether they originate from a random fraction of tumor cells. Here we show, by gene expression profiling, that human primary breast tumors are strikingly similar to the distant metastases of the same patient. Unsupervised hierarchical clustering, multidimensional scaling, and permutation testing, as well as the comparison of significantly expressed genes within a pair, reveal their genetic similarity. Our findings suggest that metastatic capability in breast cancer is an inherent feature and is not based on clonal selection.
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