ABSTRACT
BACKGROUND: Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer. PATIENTS AND METHODS: Eligible patients had locally advanced, unresectable, or metastatic HER2- breast cancer with Eastern Cooperative Group performance status of 0-2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV. RESULTS: Study patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response. CONCLUSION: The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted. TRIAL REGISTRATION: NCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Paclitaxel/therapeutic use , Receptor, ErbB-2/genetics , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: ROR1 and ROR2 are Type 1 tyrosine kinase-like orphan receptors for Wnt5a that are associated with breast cancer progression. Experimental agents targeting ROR1 and ROR2 are in clinical trials. This study evaluated whether expression levels of ROR1 or ROR2 correlated with one another or with clinical outcomes. METHODS: We interrogated the clinical significance of high-level gene expression of ROR1 and/or ROR2 in the annotated transcriptome dataset from 989 patients with high-risk early breast cancer enrolled in one of nine completed/graduated/experimental and control arms in the neoadjuvant I-SPY2 clinical trial (NCT01042379). RESULTS: High ROR1 or high ROR2 was associated with breast cancer subtypes. High ROR1 was more prevalent among hormone receptor-negative and human epidermal growth factor receptor 2-negative (HR-HER2-) tumors and high ROR2 was less prevalent in this subtype. Although not associated with pathologic complete response, high ROR1 or high ROR2 each was associated with event-free survival (EFS) in distinct subtypes. High ROR1 associated with a worse EFS in HR + HER2- patients with high post-treatment residual cancer burden (RCB-II/III) (HR 1.41, 95% CI = 1.11-1.80) but not in patients with minimal post-treatment disease (RCB-0/I) (HR 1.85, 95% CI = 0.74-4.61). High ROR2 associated with an increased risk of relapse in patients with HER2 + disease and RCB-0/I (HR 3.46, 95% CI = 1.33-9.020) but not RCB-II/III (HR 1.07, 95% CI = 0.69-1.64). CONCLUSION: High ROR1 or high ROR2 distinctly identified subsets of breast cancer patients with adverse outcomes. Further studies are warranted to determine if high ROR1 or high ROR2 may identify high-risk populations for studies of targeted therapies.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Neoadjuvant Therapy , Receptor Tyrosine Kinase-like Orphan Receptors/genetics , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Neoplasm Recurrence, Local , Gene ExpressionABSTRACT
Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in ß-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in ß-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC.
Subject(s)
Breast Neoplasms , Diabetes Mellitus, Type 2 , Extracellular Vesicles , MicroRNAs , Animals , Breast Neoplasms/pathology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Extracellular Vesicles/metabolism , Female , Glucose/metabolism , Homeostasis , Humans , Insulin/metabolism , Insulin Secretion , Mice , MicroRNAs/genetics , MicroRNAs/metabolismABSTRACT
HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.
Subject(s)
Ado-Trastuzumab Emtansine/therapeutic use , Breast Neoplasms/drug therapy , Neoadjuvant Therapy/methods , Adult , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Biomarkers, Tumor , Humans , Maytansine/therapeutic use , Middle Aged , Paclitaxel/therapeutic use , Receptor, ErbB-2/therapeutic use , Trastuzumab/therapeutic useABSTRACT
The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Neoadjuvant Therapy/mortality , Receptor, ErbB-2/metabolism , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Breast Neoplasms/pathology , Female , Follow-Up Studies , Humans , Middle Aged , Paclitaxel/administration & dosage , Phthalazines/administration & dosage , Piperazines/administration & dosage , Prognosis , Survival Rate , Young AdultABSTRACT
Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.80; P < 0.001) and OS (HR, 0.67; 95% CI, 0.50-0.90; P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4% P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.
Subject(s)
Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Circulating Tumor DNA/genetics , Disease-Free Survival , Female , Genome, Human , Humans , Male , Middle Aged , Neoplasms/drug therapy , Precision Medicine , Treatment Outcome , Young AdultABSTRACT
PURPOSE: This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC). METHODS: At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety. RESULTS: Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5-10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3-11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74-1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3-17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7-5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%). CONCLUSION: AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307.
Subject(s)
Breast Neoplasms/drug therapy , Cancer Vaccines/therapeutic use , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Cancer Vaccines/pharmacology , Double-Blind Method , Female , Humans , Middle Aged , Neoplasm Metastasis , Survival Analysis , Treatment Outcome , Vaccines, Conjugate/pharmacology , Vaccines, Conjugate/therapeutic useABSTRACT
OBJECTIVE: Anxiety and depression are common in individuals with cancer and may impact healthcare service use and costs in this population. This study examined the effects of anxiety alone, depression alone, and comorbid anxiety and depressive disorder on healthcare use and costs among patients with cancer. METHOD: This was a retrospective cohort analysis of administrative data of patients aged 18 or older with an International Classification of Diseases, Ninth Revision diagnosis of cancer. Key outcomes were any visit to emergency department (ED), any inpatient hospitalization, length of hospital stays, and annual healthcare costs 1 year from cancer diagnosis. RESULTS: A total of 13,426 patients were included. Relative to patients with neither anxiety nor depression, those with anxiety alone, depression alone, or comorbid anxiety and depression were more likely to experience an ED visit and be hospitalized. Length of hospital stays were also longer and annual healthcare costs were significantly higher in all three clinical groups. CONCLUSIONS: Cancer patients with anxiety and depression were at greater risk for ED visits and hospitalizations, experienced longer hospital stays, and accrued higher healthcare costs. Future researchers should determine whether screening and treating comorbid anxiety and depression may decrease healthcare utilization and improve turnover wellbeing among cancer patients.
Subject(s)
Depression , Neoplasms , Adolescent , Adult , Anxiety/epidemiology , Anxiety Disorders/epidemiology , Anxiety Disorders/therapy , Depression/epidemiology , Depression/therapy , Emergency Service, Hospital , Health Care Costs , Humans , Neoplasms/epidemiology , Neoplasms/therapy , Retrospective StudiesABSTRACT
BACKGROUND: We assessed breast cancer mortality in older versus younger women according to race/ethnicity, neighborhood socioeconomic status (nSES), and health insurance status. METHODS: The study included female breast cancer cases 18 years of age and older, diagnosed between 2005 and 2015 in the California Cancer Registry. Multivariable Cox proportional hazards modeling was used to generate hazard ratios (HR) of breast cancer specific deaths and 95% confidence intervals (CI) for older (60+ years) versus younger (< 60 years) patients separately by race/ethnicity, nSES, and health insurance status. RESULTS: Risk of dying from breast cancer was higher in older than younger patients after multivariable adjustment, which varied in magnitude by race/ethnicity (P-interaction< 0.0001). Comparing older to younger patients, higher mortality differences were shown for non-Hispanic White (HR = 1.43; 95% CI, 1.36-1.51) and Hispanic women (HR = 1.37; 95% CI, 1.26-1.50) and lower differences for non-Hispanic Blacks (HR = 1.17; 95% CI, 1.04-1.31) and Asians/Pacific Islanders (HR = 1.15; 95% CI, 1.02-1.31). HRs comparing older to younger patients varied by insurance status (P-interaction< 0.0001), with largest mortality differences observed for privately insured women (HR = 1.51; 95% CI, 1.43-1.59) and lowest in Medicaid/military/other public insurance (HR = 1.18; 95% CI, 1.10-1.26). No age differences were shown for uninsured women. HRs comparing older to younger patients were similar across nSES strata. CONCLUSION: Our results provide evidence for the continued disparity in Black-White breast cancer mortality, which is magnified in younger women. Moreover, insurance status continues to play a role in breast cancer mortality, with uninsured women having the highest risk for breast cancer death, regardless of age.
Subject(s)
Breast Neoplasms/ethnology , Breast Neoplasms/mortality , Healthcare Disparities , Insurance, Health , Race Factors , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Ethnicity , Female , Humans , Medicaid , Middle Aged , Social Class , United States/epidemiology , Young AdultABSTRACT
PURPOSE: To date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response. METHODS: We assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test. RESULTS: Overall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification. CONCLUSION: EGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study.
ABSTRACT
Clinical-grade next-generation sequencing (NGS) of tissue- and blood-derived circulating tumor DNA (ctDNA) allows assessment of multiple genomic alterations in patients with cancer. We analyzed ctDNA (54-70 genes) in 62 patients with advanced breast cancer (median = five prior therapies); 38 also had tissue NGS (236-315 genes). Overall, 42 of 62 patients (68%) had detectable (characterized) ctDNA alterations (variants of unknown significance excluded), and 37 of 38 (97%) had tissue alterations. The median (range) number of characterized alterations in ctDNA was 1 (0-7), and in tissue, 4 (0-17). The most common alterations in ctDNA were in TP53 (37% of patients) and PIK3CA (23%), and for tissue, TP53 (37%) and PIK3CA (24%); EGFR amplification was seen in ctDNA (11%), but not in tissue. Concordance between ctDNA and tissue appeared higher if <6 months separated the sample acquisition, although small sample size precluded statistical validation. Overall, 32 of 67 tissue alterations (48%) were also detected in ctDNA; 35 of 72 ctDNA alterations (48%) were also in tissue. Excluding estrogen receptor and ERBB2, 41 of 62 patients (66%) had potentially actionable alterations in ctDNA, and 36 of 38 (95%), in tissue (with potential actionability based on either preclinical or clinical evidence). If ≥1 genomic alteration had ctDNA ≥5%, survival was shorter than if ctDNA was <5% (median, 6.7 vs. 17.9 months; P = 0.01). In conclusion, tissue and ctDNA NGS reveal potentially actionable alterations in most patients. The genomic results of ctDNA and tissue NGS overlap, but there are differences, perhaps reflecting temporal spacing and tumor heterogeneity. ctDNA quantification also provides prognostic information.
Subject(s)
Breast Neoplasms/genetics , Circulating Tumor DNA/genetics , Genome, Human/genetics , High-Throughput Nucleotide Sequencing , Biomarkers, Tumor/blood , Breast Neoplasms/blood , Breast Neoplasms/pathology , Cell Line, Tumor , Circulating Tumor DNA/blood , Female , Genomics , Humans , Middle Aged , MutationABSTRACT
BACKGROUND: Breast cancer in younger patients is reported to be more aggressive and associated with lower survival; however, factors associated with age-specific mortality differences have not been adequately assessed. METHODS: We used data from the population-based California Cancer Registry for 38,509 younger (18-49 years) and 121,573 older (50 years and older) women diagnosed with stage I to III breast cancer, 2005-2014. Multivariable Cox regression models were used to estimate breast cancer-specific mortality rate ratios (MRR) and 95% confidence intervals (CI), stratified by tumor subtype, guideline treatment, and care at an NCI-designated cancer center (NCICC). RESULTS: Older breast cancer patients at diagnosis experienced 17% higher disease-specific mortality than younger patients, after multivariable adjustment (MRR = 1.17; 95% CI, 1.11-1.23). Higher MRRs (95% CI) were observed for older versus younger patients with hormone receptor (HR)+/HER2- (1.24; 1.14-1.35) and HR+/HER2+ (1.38; 1.17-1.62), but not for HR-/HER2+ (HR = 0.94; 0.79-1.12) nor triple-negative breast cancers (1.01; 0.92-1.11). The higher mortality in older versus younger patients was diminished among patients who received guideline-concordant treatment (MRR = 1.06; 95% CI, 0.99-1.14) and reversed among those seen at an NCICC (MRR = 0.86; 95% CI, 0.73-1.01). CONCLUSIONS: Although younger women tend to be diagnosed with more aggressive breast cancers, adjusting for these aggressive features results in older patients having higher mortality than younger patients, with variations by age, tumor subtype, receipt of guideline treatment, and being cared for at an NCICC. IMPACT: Higher breast cancer mortality in older compared with younger women could partly be addressed by ensuring optimal treatment and comprehensive patient-centered care.
Subject(s)
Breast Neoplasms/mortality , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Adult , Age Factors , Biomarkers, Tumor/analysis , Breast Neoplasms/metabolism , California/epidemiology , Female , Humans , Middle Aged , Proportional Hazards Models , Receptor, ErbB-2/genetics , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Young AdultABSTRACT
BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015. RESULTS: Of the 423 patients, 61 (14.4%) had TERT promoter mutations, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 (TP53; 39%) and KRAS and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) alterations (15% each) in this population. TERT promoter alterations were more frequent in men (P = .031) and were associated with brain cancers (P = .001), skin cancers/melanoma (P = .001), and a higher number of aberrations (P = .0001). A co-alteration analysis found that TERT promoter alterations were significantly correlated with CDKN2A/B (P = .001) and BRAF abnormalities (P = .0003). Patients harboring TERT promoter alterations or TP53 or CDKN2A/B alterations and those with 4 or more alterations demonstrated shorter survival (hazard ratio for normal TERT promoters vs aberrant ones, 0.44; P = .017). However, only a higher number of alterations remained significant in the multivariate analysis. CONCLUSIONS: Overall, TERT promoter alterations were among the most prevalent aberrations in this population, with very high rates in brain cancers (48% of patients) and melanomas (56% of patients). These aberrations frequently coexist with a high number of other aberrations, with the latter feature also significantly associated with poorer overall survival. Therapeutic options for targeting tumors with TERT promoter mutations are currently limited, although a variety of novel approaches are under development. Cancer 2018;124:1288-96. © 2017 American Cancer Society.
Subject(s)
Biomarkers, Tumor/genetics , High-Throughput Nucleotide Sequencing/methods , Mutation , Neoplasms/genetics , Promoter Regions, Genetic , Telomerase/genetics , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Neoplasms/classification , Neoplasms/pathology , Prognosis , Retrospective Studies , Survival RateABSTRACT
Efforts to identify driver mutations in cancer have largely focused on genes, whereas non-coding sequences remain relatively unexplored. Here we develop a statistical method based on characteristics known to influence local mutation rate and a series of enrichment filters in order to identify distal regulatory elements harboring putative driver mutations in breast cancer. We identify ten DNase I hypersensitive sites that are significantly mutated in breast cancers and associated with the aberrant expression of neighboring genes. A pan-cancer analysis shows that three of these elements are significantly mutated across multiple cancer types and have mutation densities similar to protein-coding driver genes. Functional characterization of the most highly mutated DNase I hypersensitive sites in breast cancer (using in silico and experimental approaches) confirms that they are regulatory elements and affect the expression of cancer genes. Our study suggests that mutations of regulatory elements in tumors likely play an important role in cancer development.Cancer driver mutations can occur within noncoding genomic sequences. Here, the authors develop a statistical approach to identify candidate noncoding driver mutations in DNase I hypersensitive sites in breast cancer and experimentally demonstrate they are regulatory elements of known cancer genes.
Subject(s)
Breast Neoplasms/genetics , Deoxyribonuclease I/metabolism , Regulatory Sequences, Nucleic Acid/genetics , Chromatin/metabolism , Chromatin Assembly and Disassembly , Female , Gene Expression Regulation, Neoplastic , Humans , Mutation/genetics , Reproducibility of Results , Sequence Deletion , Telomerase/metabolismABSTRACT
PURPOSE: There is a growing interest in using circulating tumor DNA (ctDNA) testing in patients with cancer. EXPERIMENTAL DESIGN: A total of 168 patients with diverse cancers were analyzed. Patients had digital next-generation sequencing (54 cancer-related gene panel including amplifications in ERBB2, EGFR, and MET) performed on their plasma. Type of genomic alterations, potential actionability, concordance with tissue testing, and patient outcome were examined. RESULTS: Fifty-eight percent of patients (98/168) had ≥1 ctDNA alteration(s). Of the 98 patients with alterations, 71.4% had ≥ 1 alteration potentially actionable by an FDA-approved drug. The median time interval between the tissue biopsy and the blood draw was 2.7 months for patients with ≥ 1 alteration in common compared with 14.4 months (P = 0.006) for the patients in whom no common alterations were identified in the tissue and plasma. Overall concordance rates for tissue and ctDNA were 70.3% for TP53 and EGFR, 88.1% for PIK3CA, and 93.1% for ERBB2 alterations. There was a significant correlation between the cases with ≥ 1 alteration with ctDNA ≥ 5% and shorter survival (median = 4.03 months vs. not reached at median follow-up of 6.1 months; P < 0.001). Finally, 5 of the 12 evaluable patients (42%) matched to a treatment targeting an alteration(s) detected in their ctDNA test achieved stable disease ≥ 6 months/partial remission compared with 2 of 28 patients (7.1%) for the unmatched patients, P = 0.02. CONCLUSIONS: Our initial study demonstrates that ctDNA tests provide information complementary to that in tissue biopsies and may be useful in determining prognosis and treatment. Clin Cancer Res; 22(22); 5497-505. ©2016 AACR.
Subject(s)
Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , DNA, Neoplasm/blood , Neoplasms/blood , Neoplasms/pathology , DNA, Neoplasm/genetics , ErbB Receptors/genetics , Female , Genomics , High-Throughput Nucleotide Sequencing/methods , Humans , Liquid Biopsy/methods , Male , Medical Oncology/methods , Middle Aged , Neoplasms/genetics , Phosphatidylinositol 3-Kinases/genetics , Receptor, ErbB-2/genetics , Retrospective Studies , Tumor Suppressor Protein p53/geneticsABSTRACT
Analysis of cell-free DNA using next-generation sequencing (NGS) is a powerful tool for the detection/monitoring of alterations present in circulating tumor DNA (ctDNA). Plasma extracted from 171 patients with a variety of cancers was analyzed for ctDNA (54 genes and copy number variants (CNVs) in three genes (EGFR, ERBB2 and MET)). The most represented cancers were lung (23%), breast (23%), and glioblastoma (19%). Ninety-nine patients (58%) had at least one detectable alteration. The most frequent alterations were TP53 (29.8%), followed by EGFR (17.5%), MET (10.5%), PIK3CA (7%), and NOTCH1 (5.8%). In contrast, of 222 healthy volunteers, only one had an aberration (TP53). Ninety patients with non-brain tumors had a discernible aberration (65% of 138 patients; in 70% of non-brain tumor patients with an alteration, the anomaly was potentially actionable). Interestingly, nine of 33 patients (27%) with glioblastoma had an alteration (6/33 (18%) potentially actionable). Overall, sixty-nine patients had potentially actionable alterations (40% of total; 69.7% of patients (69/99) with alterations); 68 patients (40% of total; 69% of patients with alterations), by a Food and Drug Administration (FDA) approved drug. In summary, 65% of diverse cancers (as well as 27% of glioblastomas) had detectable ctDNA aberration(s), with the majority theoretically actionable by an approved agent.
Subject(s)
Biomarkers, Tumor/genetics , DNA Copy Number Variations/genetics , DNA, Neoplasm/genetics , Mutation/genetics , Neoplasms/genetics , Neoplastic Cells, Circulating/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Biopsy , Class I Phosphatidylinositol 3-Kinases , ErbB Receptors/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-met/genetics , Receptor, Notch1/genetics , Retrospective Studies , Tumor Suppressor Protein p53/genetics , Young AdultABSTRACT
By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a "matched" versus "unmatched" therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a "matched" therapy, 93 (26.8%) with an "unmatched" therapy. More patients in the matched group achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR), 34.5% vs. 16.1%, (P ≤ 0.020 multivariable or propensity score methods). Matched patients had a longer median progression-free survival (PFS; 4.0 vs. 3.0 months, P = 0.039 in the Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P = 0.009); however, this shortening was not observed in the matched patients (P = 0.595). Furthermore, 45.3% of the matched patients (24/53) had a PFS2/PFS1 ratio ≥1.3 compared with 19.3% of patients (11/57) in the unmatched group (P = 0.004 univariable and P ≥ 0.057 in multivariable/propensity score analysis). Patients with a "matching-score" (the number of matched drugs divided by the number of aberrations; unmatched patients had a score of zero) > 0.2 had a median overall survival (OS) of 15.7 months compared with 10.6 months when their matching-score was ≤ 0.2, (P = 0.040 in the Cox regression model). Matched versus unmatched patients had higher rates of SD ≥ 6 months/PR/CR and longer PFS, and improvement in OS correlated with a higher matching score in multivariable analysis. Mol Cancer Ther; 15(4); 743-52. ©2016 AACR.
Subject(s)
Medical Oncology , Neoplasms/diagnosis , Neoplasms/therapy , Precision Medicine , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , California , Female , Gene Expression Profiling , Genomics/methods , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Molecular Targeted Therapy , Neoplasms/genetics , Neoplasms/mortality , Prognosis , Propensity Score , Proportional Hazards Models , Retrospective Studies , Treatment OutcomeABSTRACT
Some communities and populations lack access to genetic cancer risk assessment (GCRA) and testing. This is particularly evident in safety-net institutions, which serve a large segment of low-income, uninsured individuals. We describe the experience of a safety-net clinic with limited resources in providing GCRA and BRCA1/2 testing. We compared the proportion and characteristics of high-risk women who were offered and underwent GCRA and genetic testing. We also provide a description of the mutation profile for affected women. All 125 patients who were offered GCRA accepted to undergo GCRA. Of these, 72 % had a breast cancer diagnosis, 70 % were Hispanic, 52.8 % were non-English speakers, and 66 % did not have health insurance. Eighty four (67 %) were offered genetic testing and 81 (96 %) agreed. Hispanic women, those with no medical insurance, and those with a family history of breast cancer were significantly more likely to undergo testing (p > 0.01). Twelve of 81 (15 %) patients were found to have deleterious mutations, seven BRCA1, and five BRCA2. Our experience shows that it is possible to offer GCRA and genetic testing even in the setting of limited resources for these services. This is important given that a large majority of the low-income women in our study agreed to undergo counseling and testing. Our experience could serve as a model for similar low-resource safety-net health settings.
ABSTRACT
Tumor sequencing has revolutionized oncology, allowing for detailed interrogation of the molecular underpinnings of cancer at an individual level. With this additional insight, it is increasingly apparent that not only do tumors vary within a sample (tumor heterogeneity), but also that each patient's individual tumor is a constellation of unique molecular aberrations that will require an equally unique personalized therapeutic regimen. We report here the results of 439 patients who underwent Clinical Laboratory Improvement Amendment (CLIA)-certified next generation sequencing (NGS) across histologies. Among these patients, 98.4% had a unique molecular profile, and aside from three primary brain tumor patients with a single genetic lesion (IDH1 R132H), no two patients within a given histology were molecularly identical. Additionally, two sets of patients had identical profiles consisting of two mutations in common and no other anomalies. However, these profiles did not segregate by histology (lung adenocarcinoma-appendiceal cancer (KRAS G12D and GNAS R201C), and lung adenocarcinoma-liposarcoma (CDK4 and MDM2 amplification pairs)). These findings suggest that most advanced tumors are molecular singletons within and between histologies, and that tumors that differ in histology may still nonetheless exhibit identical molecular portraits, albeit rarely.