ABSTRACT
The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID-19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID-19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full-scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre-pandemic cancer care delivery.
Subject(s)
COVID-19 , Cancer Care Facilities/organization & administration , Delivery of Health Care/organization & administration , Neoplasms/therapy , COVID-19/complications , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Testing , California/epidemiology , Global Health , Humans , Infection Control/methods , Infection Control/organization & administration , Neoplasms/complications , Neoplasms/diagnosis , Pandemics , Telemedicine/methods , Telemedicine/organization & administrationABSTRACT
BACKGROUND: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in non-small cell lung cancer (NSCLC). Based on preclinical demonstration of additive cytotoxicity, we evaluated the safety and efficacy of combining pemetrexed and nanoparticle albumin bound (nab) paclitaxel with a focus on NSCLC for phase II expansion. METHODS: A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: pemetrexed 500 mg/m(2) day 1 and nab-paclitaxel day 1 at 180, 220, & 260 mg/m(2) every 21 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. RESULTS: Planned dose escalation was completed without reaching the MTD. The RP2D was pemetrexed 500 mg/m(2) and nab-paclitaxel 260 mg/m(2). The phase II portion accrued 37 pts before early closure due to increasing first-line pemetrexed/platinum doublet use in non-squamous NSCLC. In 31 assessable phase II patients there were 5 partial responses, 12 stable disease, 14 progressive disease. The median overall survival was 8.8 months; progressive disease 4.4 months and disease control 15.6 months. CONCLUSIONS: Pemetrexed 500 mg/m(2) day 1 with nab-paclitaxel 260 mg/m(2) was feasible and well tolerated. The phase II component demonstrated activity in second/third-line therapy of advanced NSCLC; response rate 14% and disease control rate 46%. Treatment practice patterns of advanced NSCLC have evolved; further trials of this regimen are not planned.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Neoplasms/drug therapy , Aged , Albumins/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Administration Schedule , Female , Glutamates/administration & dosage , Guanine/administration & dosage , Guanine/analogs & derivatives , Humans , Male , Maximum Tolerated Dose , Middle Aged , Paclitaxel/administration & dosage , PemetrexedABSTRACT
Alteration in glycosylation has been observed in cancer. However, monitoring glycosylation changes during breast cancer progression is difficult in humans. In this study, we used a well-characterized transplantable breast tumor mouse model, the mouse mammary tumor virus-polyoma middle T antigen, to observe early changes in glycosylation. We have previously used the said mouse model to look at O-linked glycosylation changes with breast cancer. In this glycan biomarker discovery study, we examined N-linked glycan variations during breast cancer progression of the mouse model but this time doubling the number of mice and blood draw points. N-glycans from total mouse serum glycoproteins were profiled using matrix-assisted laser desorption/ionization Fourier transform-ion cyclotron resonance mass spectrometry at the onset, progression, and removal of mammary tumors. We observed four N-linked glycans, m/z 1339.480 (Hex(3)HexNAc), 1485.530 (Hex(3)HexNAc(4)Fuc), 1809.639 (Hex(5)HexNAc(4)Fuc), and 1905.630 (Man(9)), change in intensity in the cancer group but not in the control group. In a separate study, N-glycans from total human serum glycoproteins of breast cancer patients and controls were also profiled. Analysis of human sera using an internal standard showed the alteration of the low-abundant high-mannose glycans, m/z 1419.475, 1581.528, 1743.581, 1905.634 (Man(6-9)), in breast cancer patients. A key observation was the elevation of a high-mannose type glycan containing nine mannoses, Man(9), m/z 1905.630 in both mouse and human sera in the presence of breast cancer, suggesting an incompletion of the glycosylation process that normally trims back Man(9) to produce complex and hybrid type oligosaccharides.
Subject(s)
Breast Neoplasms/blood , Breast Neoplasms/pathology , Disease Progression , Mannose/blood , Polysaccharides/blood , Animals , Carbohydrate Conformation , Female , Humans , Mannose/chemistry , Mice , Neoplasm Metastasis , Polysaccharides/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
BACKGROUND: Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC. METHODS: The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor-positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1-14, and capecitabine, 1,500 mg twice daily on days 8-21, in 21-day cycles. RESULTS: In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7-8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1-22.0 months). The RR was 36% (95% CI, 26%-48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%-48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths. CONCLUSIONS: PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/mortality , Capecitabine , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Humans , Middle Aged , Mucin-1/analysis , Prospective StudiesABSTRACT
A population-based cohort was used to determine the incidence and risk factors associated with development of venous thromboembolism (VTE) among Californians diagnosed with acute leukemia between 1993 to 1999. Principal outcomes were deep vein thrombosis in both the lower and upper extremities, pulmonary embolism, and mortality. Among 5394 cases with acute myelogenous leukemia (AML), the 2-year cumulative incidence of VTE was 281 (5.2%). Sixty-four percent of the VTE events occurred within 3 months of AML diagnosis. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Among 2482 cases with acute lymphoblastic leukemia (ALL), the 2-year incidence of VTE in ALL was 4.5%. Risk factors for VTE were presence of a central venous catheter, older age, and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. The incidence of VTE in acute leukemia is appreciable, and is comparable with the incidence in many solid tumors.
Subject(s)
Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Venous Thromboembolism/complications , Venous Thromboembolism/epidemiology , Adult , Female , Humans , Male , Middle Aged , Models, Biological , Risk Factors , Survival RateABSTRACT
MOTIVATION: The development of better tests to detect cancer in its earliest stages is one of the most sought-after goals in medicine. Especially important are minimally invasive tests that require only blood or urine samples. By profiling oligosaccharides cleaved from glycosylated proteins shed by tumor cells into the blood stream, we hope to determine glycan profiles that will help identify cancer patients using a simple blood test. The data in this article were generated using matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI FT-ICR MS). We have developed novel methods for analyzing this type of mass spectrometry data and applied it to eight datasets from three different types of cancer (breast, ovarian and prostate). RESULTS: The techniques we have developed appear to be effective in the analysis of MALDI FT-ICR MS data. We found significant differences between control and cancer groups in all eight datasets, including two structurally related compounds that were found to be significantly different between control and cancer groups in all three types of cancer studied.
Subject(s)
Biomarkers, Tumor/blood , Neoplasms/metabolism , Polysaccharides/blood , Software , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Algorithms , Cyclotrons , Fourier Analysis , Humans , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/instrumentationABSTRACT
BACKGROUND: Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. METHODS: Patients with stage I-III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. RESULTS: A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). CONCLUSIONS: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.
Subject(s)
Breast Neoplasms/drug therapy , Diphosphonates/administration & dosage , Administration, Oral , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/adverse effects , Bone Neoplasms/prevention & control , Bone Neoplasms/secondary , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Clodronic Acid/administration & dosage , Clodronic Acid/adverse effects , Diphosphonates/adverse effects , Disease-Free Survival , Female , Humans , Ibandronic Acid/administration & dosage , Ibandronic Acid/adverse effects , Infusions, Intravenous , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Survival Rate , Treatment Outcome , Zoledronic Acid/administration & dosage , Zoledronic Acid/adverse effectsABSTRACT
PURPOSE: The study was undertaken to develop and evaluate the potential of an integrin αvß6-binding peptide (αvß6-BP) for noninvasive imaging of a diverse range of malignancies with PET. EXPERIMENTAL DESIGN: The peptide αvß6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired αvß6-expressing and αvß6-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired αvß6-expressing and αvß6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. RESULTS: [18F]αvß6-BP displayed excellent affinity and selectivity for the integrin αvß6 in vitro [IC50(αvß6) = 1.2 nmol/L vs IC50(αvß3) >10 µmol/L] in addition to rapid target-specific cell binding and internalization (72.5% ± 0.9% binding and 52.5% ± 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvß6-BP was rapid, primarily via the kidneys. In patients, [18F]αvß6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvß6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. CONCLUSIONS: The clinical impact of [18F]αvß6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.
Subject(s)
Antigens, Neoplasm/isolation & purification , Carrier Proteins/isolation & purification , Integrins/isolation & purification , Pancreatic Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography , Animals , Antigens, Neoplasm/pharmacology , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/pathology , Bone Neoplasms/secondary , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Brain Neoplasms/secondary , Carrier Proteins/pharmacology , Female , Heterografts , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mice , Neoplasm Metastasis , Pancreatic Neoplasms/pathology , Radiopharmaceuticals/pharmacologyABSTRACT
BACKGROUND: Imatinib mesylate is a potent inhibitor of the Bcr-Abl, c-Kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. On the basis of variable expression of c-Kit and PDGFR in breast cancer and of in vitro data supporting synergy between imatinib and capecitabine, the Southwest Oncology Group conducted a phase II trial of the combination in metastatic breast cancer. PATIENTS AND METHODS: Eligible patients had progressive, measurable metastatic breast cancer and receivedSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
, Breast Neoplasms/pathology
, Deoxycytidine/analogs & derivatives
, Fluorouracil/analogs & derivatives
, Piperazines/administration & dosage
, Pyrimidines/administration & dosage
, Receptors, Platelet-Derived Growth Factor/analysis
, Administration, Oral
, Adult
, Aged
, Benzamides
, Breast Neoplasms/chemistry
, Capecitabine
, Deoxycytidine/administration & dosage
, Drug Synergism
, Female
, Fluorouracil/administration & dosage
, Humans
, Imatinib Mesylate
, Middle Aged
, Proto-Oncogene Proteins c-kit/analysis
, Receptor, Platelet-Derived Growth Factor beta/analysis
ABSTRACT
PURPOSE: There is limited data on prognosis of node-negative (N0), HER2-positive (HER2+) small breast cancers. We evaluated breast cancer-specific survival (BCSS) among women diagnosed with T1a/T1b, N0 tumors in California between 2000-2004 and 2005-2012, eras before and after approval of adjuvant trastuzumab. PATIENTS AND METHODS: 45,346 women diagnosed with T1a/b, N0 tumors between January 1, 2000 and December 31, 2012 were identified in the California Cancer Registry (CCR); approximately 10% were HER2â¯+â¯, and 80% hormone receptor positive (ER and/or PR+). Primary outcome was BCSS, analyzed in 2000-2004 and 2005-2012. Multivariable Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for mortality, and separately conducted for hormone receptor positive and negative tumors. Kaplan-Meier curves compared BCSS by HER2 status. RESULTS: While BCSS in this cohort exceeded 90%, a significantly higher hazard of breast cancer death was observed in women with HER2+ tumors in the 2000-2004 era. There was no difference in outcomes between T1a and T1b tumors. Women with ER/PR+ tumors had lower hazards of death in both eras, but HER2+ tumors were associated with a higher hazard of death in the 2000-2004 era. Among women with hormone receptor negative tumors, HER2 positive disease was associated with a lower hazard of death in the 2005-2012 era. CONCLUSION: Within this large cohort of T1a/b N0 breast cancers from the CCR, HER2+ tumors were associated with a significantly worse BCSS in the era before adjuvant trastuzumab. A balanced discussion regarding HER2-directed therapies is needed between patient and clinician.
ABSTRACT
PURPOSE: Few population-based studies have focused on cardiovascular disease (CVD) risk in adolescent and young adult (AYA; 15-39 years) cancer survivors and none have considered whether CVD risk differs by sociodemographic factors. METHODS: Analyses focused on 79,176 AYA patients diagnosed with 14 first primary cancers in 1996-2012 and surviving > 2 years after diagnosis with follow-up through 2014. Data were obtained from the California Cancer Registry and State hospital discharge data. CVD included coronary artery disease, heart failure, and stroke. The cumulative incidence of developing CVD accounted for the competing risk of death. Multivariable Cox proportional hazards regression evaluated factors associated with CVD and the impact of CVD on mortality. RESULTS: Overall, 2249 (2.8%) patients developed CVD. Survivors of central nervous system cancer (7.3%), acute lymphoid leukemia (6.9%), acute myeloid leukemia (6.8%), and non-Hodgkin lymphoma (4.1%) had the highest 10-year CVD incidence. In multivariable models, African-Americans (hazard ratio (HR) = 1.55, 95% confidence interval (CI) = 1.33-1.81; versus non-Hispanic Whites), those with public/no health insurance (HR = 1.78, 95% CI = 1.61-1.96; versus private) and those who resided in lower socioeconomic status neighborhoods had a higher CVD risk. These sociodemographic differences in CVD incidence were apparent across most cancer sites. The risk of death was increased by eightfold or higher among AYAs who developed CVD. CONCLUSION: While cancer therapies are known to increase the risk of CVD, this study additionally shows that CVD risk varies by sociodemographic factors. IMPLICATIONS FOR CANCER SURVIVORS: The identification and mitigation of CVD risk factors in these subgroups may improve long-term patient outcomes.
Subject(s)
Cancer Survivors/statistics & numerical data , Cardiovascular Diseases/epidemiology , Adolescent , Adult , Black or African American/statistics & numerical data , Age Factors , California/epidemiology , Cohort Studies , Female , Humans , Incidence , Male , Neoplasms/epidemiology , Registries , Retrospective Studies , White People/statistics & numerical data , Young AdultABSTRACT
BACKGROUND: The incidence of venous thromboembolism after diagnosis of specific cancers and the effect of thromboembolism on survival are not well defined. METHODS: The California Cancer Registry was linked to the California Patient Discharge Data Set to determine the incidence of venous thromboembolism among cancer cases diagnosed between 1993 and 1995. The incidence and timing of thromboembolism within 1 and 2 years of cancer diagnosis and the risk factors associated with thromboembolism and death were determined. RESULTS: Among 235 149 cancer cases, 3775 (1.6%) were diagnosed with venous thromboembolism within 2 years, 463 (12%) at the time cancer was diagnosed and 3312 (88%) subsequently. In risk-adjusted models, metastatic disease at the time of diagnosis was the strongest predictor of thromboembolism. Expressed as events per 100 patient-years, the highest incidence of thromboembolism occurred during the first year of follow-up among cases with metastatic-stage pancreatic (20.0), stomach (10.7), bladder (7.9), uterine (6.4), renal (6.0), and lung (5.0) cancer. Adjusting for age, race, and stage, diagnosis of thromboembolism was a significant predictor of decreased survival during the first year for all cancer types (hazard ratios, 1.6-4.2; P<.01). CONCLUSIONS: The incidence of venous thromboembolism varied with cancer type and was highest among patients initially diagnosed with metastatic-stage disease. The incidence rate of thromboembolism decreased over time. Diagnosis of thromboembolism during the first year of follow-up was a significant predictor of death for most cancer types and stages analyzed. For some types of cancer, the incidence of thromboembolism was sufficiently high to warrant prospective clinical trials of primary thromboprophylaxis.
Subject(s)
Neoplasms/complications , Neoplasms/mortality , Thromboembolism/epidemiology , Thromboembolism/etiology , Aged , Female , Humans , Incidence , Male , Middle Aged , Multivariate Analysis , Survival RateABSTRACT
Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome.Experimental Design: Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome.Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit.Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066-76. ©2017 AACR.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Benzimidazoles/administration & dosage , Breast Neoplasms/drug therapy , Carboplatin/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzimidazoles/adverse effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , California , Carboplatin/adverse effects , Combined Modality Therapy , Disease-Free Survival , Female , Germ-Line Mutation , Humans , Middle Aged , Neoplasm Metastasis , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/adverse effectsABSTRACT
This study describes the development of a rapid and practical real-time RT-PCR method to quantify ribonucleotide reductase M2 (RRM2) mRNA in tumor and peripheral white blood cells (WBCs) from patients treated with GTI-2040, an antisense drug currently in clinical trials. In order to assess target down-regulation by GTI-2040, RRM2 mRNA expression levels were analyzed in pre- and post-treatment samples from a phase II clinical trial of GTI-2040 combined with capecitabine in patients with metastatic breast cancer. Target gene RRM2 mRNA levels were evaluated using quantitative RT-PCR method: real-time PCR (TaqMan) with fluorescein labeled probes on an ABI 7900HT instrument, with additional post-processing of the data to adjust for differences in total RNA in-put across the samples. Data are presented from a patient for whom both biopsy and PBMC samples were available, demonstrating applicability of this reproducible, highly sensitive real-time RT-PCR method for the detection and quantification of mRNAs for RRM2 in human WBC and tissue samples. By providing quantitative measurement of changes in target gene expression, this method may provide an opportunity to determine the correlation between target response to GTI-2040 antisense and clinical response in patients. Furthermore this assay may assess whether WBC samples are an appropriate surrogate tissue for approximating target down-regulation in the tumor.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/genetics , RNA, Messenger/metabolism , Ribonucleoside Diphosphate Reductase/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/analogs & derivatives , Gene Expression Regulation, Neoplastic/drug effects , Humans , Oligodeoxyribonucleotides , Oligonucleotides, Antisense/administration & dosage , Reverse Transcriptase Polymerase Chain Reaction/instrumentation , Reverse Transcriptase Polymerase Chain Reaction/methods , Ribonucleoside Diphosphate Reductase/antagonists & inhibitors , Ribonucleoside Diphosphate Reductase/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
PURPOSE: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. EXPERIMENTAL DESIGN: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. RESULTS: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. CONCLUSIONS: 111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Paclitaxel/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/radiotherapy , Radioimmunotherapy/methods , Adult , Aged , Aged, 80 and over , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/therapeutic use , Bone Neoplasms/prevention & control , Bone Neoplasms/secondary , Breast Neoplasms/pathology , Cathepsins/metabolism , Combined Modality Therapy , Cyclosporine/metabolism , Cyclosporine/therapeutic use , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Female , Heterocyclic Compounds, 1-Ring/chemistry , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Humans , Indium Radioisotopes/chemistry , Indium Radioisotopes/pharmacokinetics , Indium Radioisotopes/therapeutic use , Male , Mice , Middle Aged , Neutropenia/etiology , Paclitaxel/adverse effects , Prostatic Neoplasms/pathology , Radioimmunotherapy/adverse effects , Soft Tissue Neoplasms/prevention & control , Soft Tissue Neoplasms/secondary , Treatment Outcome , Yttrium Radioisotopes/chemistry , Yttrium Radioisotopes/pharmacokinetics , Yttrium Radioisotopes/therapeutic useABSTRACT
BACKGROUND: It is unclear how frequently unprovoked venous thromboembolism (VTE) reflects the presence of an occult cancer. METHODS: The California Cancer Registry was used to identify diagnosed cases of 19 common malignancies during a 6-year period. Cases were linked to a hospital discharge database to identify incident VTE events in the year before the cancer diagnosis date. The standardized incidence ratio (SIR) of unprovoked VTE was determined by using the age-, race-, and sex-specific incidence rates in California. RESULTS: Among 528,693 cancer cases, 596 (0.11%) were associated with a diagnosis of unprovoked VTE within 1 year of the cancer diagnosis, compared with 443.0 expected cases (SIR, 1.3; 95% confidence interval, 1.2-1.5; P<.001). Among cases with metastatic-stage cancer, the SIR was 2.3 (95% confidence interval, 2.0-2.6; P<.001), whereas for all other stages, the SIR was 1.07 (95% confidence interval, 0.97-1.18; P = .09). The incidence of preceding VTE was increased over that expected only during the 4-month period immediately preceding the cancer diagnosis date (P<.001). Only 7 cancer types were associated with a significantly elevated SIR: acute myelogenous leukemia; non-Hodgkin lymphoma; and renal cell, ovarian, pancreatic, stomach, and lung cancer (SIR range, 1.8-4.2). CONCLUSIONS: In the year preceding the diagnosis of cancer, the number of cases with unprovoked VTE was modestly higher than expected, and almost all of the unexpected VTE cases were associated with a diagnosis of metastatic-stage cancer within 4 months. Given the timing and advanced stage of the unexpected cases, it is unlikely that earlier diagnosis of these cancers would have significantly improved long-term survival.
Subject(s)
Neoplasms/epidemiology , Venous Thrombosis/epidemiology , Adult , Aged , Breast Neoplasms/epidemiology , California/epidemiology , Carcinoma, Renal Cell/epidemiology , Cohort Studies , Colonic Neoplasms/epidemiology , Comorbidity , Female , Humans , Incidence , Kidney Neoplasms/epidemiology , Leukemia, Myeloid/epidemiology , Lung Neoplasms/epidemiology , Lymphoma, Non-Hodgkin/epidemiology , Male , Middle Aged , Ovarian Neoplasms/epidemiology , Pancreatic Neoplasms/epidemiology , Prostatic Neoplasms/epidemiology , Stomach Neoplasms/epidemiology , Time FactorsABSTRACT
The tumor suppressor gene product BRCA1 is a component of the RNA polymerase II (pol II) holoenzyme that is involved, through binding to various regulatory proteins, in either activation or repression of transcription. Using a yeast two-hybrid screen, we have identified a human zinc-finger-containing protein NUFIP that interacts with BRCA1. The ubiquitous, stably expressed, nuclear protein NUFIP specifically stimulates activator-independent pol II transcription in vitro and in vivo. Immunodepletion of the endogenous NUFIP causes a marked decrease of pol II transcription, which is then shown to be restored by stable complex of ectopically produced NUFIP and associated factors. NUFIP not only interacts with BRCA1 but also associates with the positive elongation factor P-TEFb through interaction with the regulatory Cyclin T1 subunit. Cyclin T1 is required for BRCA1- and NUFIP-dependent synergistic activation of pol II transcription in 293 cells. Mutation of the zinc-finger domain abolishes the NUFIP-mediated transcriptional activation. We show that NUFIP is associated with preinitiation complexes, open transcription complexes, and elongation complexes. In addition, NUFIP facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes in vitro.
Subject(s)
BRCA1 Protein/physiology , Nuclear Proteins/metabolism , Positive Transcriptional Elongation Factor B/metabolism , RNA Polymerase II/metabolism , RNA-Binding Proteins/metabolism , Transcription, Genetic , Blotting, Western , Cell Line , Cell Line, Tumor , Cell Nucleus/metabolism , Cyclin T , Cyclins/chemistry , Cyclins/metabolism , Dose-Response Relationship, Drug , Genes, Reporter , Glutathione Transferase/metabolism , HeLa Cells , Humans , Models, Biological , Nuclear Proteins/physiology , Precipitin Tests , Promoter Regions, Genetic , Protein Binding , RNA Polymerase I/metabolism , RNA Polymerase III/metabolism , RNA-Binding Proteins/physiology , Recombinant Fusion Proteins/metabolism , Transcriptional Activation , Transfection , Two-Hybrid System Techniques , Zinc Fingers , beta-Galactosidase/metabolismABSTRACT
PURPOSE: To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. PATIENTS AND METHODS: A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. RESULTS: Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2) -negative tumors (P = .067), with no differences seen with hormone receptor-positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). CONCLUSION: Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms, Male/drug therapy , Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Breast Neoplasms, Male/pathology , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Febrile Neutropenia/chemically induced , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Proportional Hazards Models , Young AdultABSTRACT
The medical management of invasive breast cancer has evolved based on the recognition that surgery alone was associated with few long-term cures. This Update will review the current status of breast cancer medical management in three areas: prevention in individuals with an elevated risk, adjuvant (postoperative) treatment of early breast cancer, and treatment principles in metastatic disease. Tamoxifen has emerged as a promising agent in the treatment of women at an increased risk for breast cancer and in those with in situ disease. However, the risks of treatment must be carefully weighed against the benefits in these cohorts of women with an excellent overall prognosis. This same principle can be applied to the use of adjuvant treatment in early invasive breast cancer, where the goal is cure. Adjuvant polychemotherapy is recommended in women considered at high-risk for relapse and death. In addition, women with hormone-sensitive breast cancer are offered adjuvant taxmoxifen. Nonetheless, there are some patients with low-risk disease or those with significant co-morbidities that are unlikely to benefit from adjuvant therapies and likely to sustain toxicities. The treatment goal in metastatic breast cancer is focused on palliation of symptoms as fewer than 10% of such patients achieve 5-year survival. However, novel targeted therapies are changing the treatment armamentarium and hold great promise. These new directions of treatment will be discussed as well as areas of controversy.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma, Intraductal, Noninfiltrating/drug therapy , Aged , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Clinical Trials as Topic , Combined Modality Therapy , Female , Humans , Middle Aged , Neoadjuvant Therapy , Prognosis , Risk Factors , Time FactorsABSTRACT
PURPOSE: CALGB 40302 sought to determine whether lapatinib would improve progression-free survival (PFS) among women with hormone receptor-positive metastatic breast cancer treated with fulvestrant. PATIENTS AND METHODS: Eligible women had estrogen receptor-positive and/or progesterone receptor-positive tumors, regardless of human epidermal growth factor receptor 2 (HER2) status, and prior aromatase inhibitor treatment. Patients received fulvestrant 500 mg intramuscularly on day 1, followed by 250 mg on days 15 and 28 and every 4 weeks thereafter, and either lapatinib 1,500 mg or placebo daily. The study planned to accrue 324 patients and was powered for a 50% improvement in PFS with lapatinib from 5 to 7.5 months. RESULTS: At the third planned interim analysis, the futility boundary was crossed, and the data and safety monitoring board recommend study closure, having accrued 295 patients. At the final analysis, there was no difference in PFS (hazard ratio [HR] of placebo to lapatinib, 1.04; 95% CI, 0.82 to 1.33; P = .37); median PFS was 4.7 months for fulvestrant plus lapatinib versus 3.8 months for fulvestrant plus placebo. There was no difference in overall survival (OS) (HR, 0.91; 95% CI, 0.68 to 1.21; P = .25). For HER2-normal tumors, median PFS did not differ by treatment arm (4.1 v 3.8 months). For HER2-positive tumors, lapatinib was associated with longer median PFS (5.9 v 3.3 months), but the differential treatment effect by HER2 status was not significant (P = .53). The most frequent toxicities were diarrhea, fatigue, and rash associated with lapatinib. CONCLUSION: Adding lapatinib to fulvestrant does not improve PFS or OS in advanced ER-positive breast cancer and is more toxic.