Showing papers by "Karla V. Ballman published in 2015"
TL;DR: To demonstrate that a biomarker is predictive of treatment benefit, the study requires biomarker status on all patients as well as patients who were treated with the agent of interest and patients not so treated, preferably in the context of a randomized study.
Abstract: To demonstrate that a biomarker is predictive of treatment benefit, the study requires biomarker status on all patients as well as patients who were treated with the agent of interest and patients not so treated, preferably in the context of a randomized study. A formal statistical test of the treatment-by-biomarker interaction should be significant. To establish whether a marker is purely prognostic, it needs to be demonstrated that there is a significant association between the biomarker and outcome, regardless of treatment, and that treatment effects do not depend on the biomarker. Finally, a biomarker may have both predictive and prognostic implications. These concepts are summarized in Figure 2.
334 citations
TL;DR: The initiation of an ERAS pathway significantly decreased hospital LOS in this study and significantly decreased the amount of opioids used postoperatively by 71%, without a consequent increase in patient-reported pain.
Abstract: Summary Background Enhanced recovery after surgery (ERAS) pathways have been shown in multiple surgical specialties to decrease hospital length of stay (LOS) after surgery, but they have not been described for patients undergoing microvascular breast reconstruction. Study design A standardized ERAS pathway was developed through multidisciplinary collaboration which addressed all phases of surgical care for patients undergoing free-flap breast reconstruction using an abdominal donor site. Two surgeons used the ERAS pathway, and results were compared with a historical cohort of the same 2 surgeons' patients treated by traditional care after surgery (TRAS). All patients underwent surgery between September 2010 and September 2013. The primary outcome measure was hospital LOS. Results A total of 100 patients were analyzed: 49 in the ERAS cohort, and 51 in the TRAS cohort, with a total of 181 flaps. Mean hospital LOS was shorter with ERAS than TRAS (3.9 vs 5.5 days; P P P = 0.21). Conclusions The initiation of an ERAS pathway significantly decreased hospital LOS in our study. The pathway also significantly decreased the amount of opioids used postoperatively by 71%, without a consequent increase in patient-reported pain.
183 citations
TL;DR: Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer.
Abstract: Purpose To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voti...
181 citations
TL;DR: AUS is recommended after chemotherapy to guide axillary surgery and an FNR of 9.8% with the combination of AUS andSLN surgery would be acceptable for the adoption of SLN surgery for women with node-positive breast cancer treated with neoadjuvant chemotherapy.
Abstract: Purpose The American College of Surgeons Oncology Group Z1071 trial reported a 12.6% false-negative rate (FNR) for sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy (NAC) in cN1 disease. Patients were not selected for surgery based on response, but a secondary end point was to determine whether axillary ultrasound (AUS) after NAC after fine-needle aspiration cytology can identify abnormal nodes and guide patient selection for SLN surgery. Patients and Methods Patients with T0-4, N1-2, M0 breast cancer underwent AUS after neoadjuvant chemotherapy. AUS images were centrally reviewed and classified as normal or suspicious lymph nodes. AUS findings were tested for association with pathologic nodal status and SLN FNR. The impact of AUS results to select patients for SLN surgery to reduce the FNR was assessed. Results Postchemotherapy AUS images were reviewed for 611 patients. One hundred thirty (71.8%) of 181 AUS-suspicious patients were node positive at surgery compared with 243 (56.5%) of 430 AUS-normal patients (P .001). Patients with AUS-suspicious nodes had a greater number of positive nodes and greater metastasis size (P .001). The SLN FNR was not different based on AUS results; however, using a strategy where only patients with normal AUS undergo SLN surgery would potentially reduce the FNR in Z1071 patients with two SLNs removed from 12.6% to 9.8% when preoperative AUS results are considered as part of SLN surgery.
180 citations
TL;DR: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS, and initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to S RS.
Abstract: LBA4 Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. Methods: Patients with 1-3 brain metastases, each 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. Results: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), dela...
128 citations
TL;DR: The data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-F OLR1 therapy, and may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.
Abstract: Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.
101 citations
TL;DR: Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation and is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparIB combination in patients with GBM.
Abstract: BACKGROUND Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction. RESULTS The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines. CONCLUSION Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.
98 citations
TL;DR: Women with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) -positive breast cancer treated in randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastzumab.
Abstract: Purpose We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) –positive breast cancer treated in randomized trials. Methods A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) –positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status. Results Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with...
90 citations
TL;DR: Although there was no predictable pattern of coagulopathy observed in each patient after trauma, those who reached extreme values did so relatively early after injury, and these findings should be taken into account when designing risk model tools involving coagulation laboratory parameters.
Abstract: OBJECTIVEThe two sides of trauma-induced coagulopathy, the hypocoagulable and the hypercoagulable states, are poorly understood. To identify potential mechanisms for venous thromboembolism and bleeding after acute trauma, we estimated changes in circulating procoagulant microparticles (MPs) and thro
47 citations
TL;DR: Estrogen receptor (ER) status and grade significantly stratified patients with stage I disease with respect to RFS, DSS, and OS and are better discriminants of survival than the presence of small-volume nodal metastases.
Abstract: Purpose The seventh edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer differentiates patients with T1 tumors and lymph node micrometastases (stage IB) from patients with T1 tumors and negative nodes (stage IA) This study was undertaken to determine the utility of the stage IB designation Patients and Methods The following two cohorts of patients with breast cancer were identified: 3,474 patients treated at The University of Texas MD Anderson Cancer Center from 1993 to 2007 and 4,590 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial Clinicopathologic and outcomes data were recorded, and disease was staged according to the seventh edition AJCC staging system Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were determined using the Kaplan-Meier method and compared using the log-rank test Results Median follow-up times were 61 years and 90 years for the MD Anderson Cancer Center and ACOSO
40 citations
TL;DR: Decline in QOL and cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS, and initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to S RS.
Abstract: BACKGROUND: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. METHODS: Patients with 1-3 brain metastases, each 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. RESULTS: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (91.7% vs. 63.5% respectively, p = 0.0007). There was more deterioration in the WBRT + SRS arm in immediate recall (30% vs. 8%, p = 0.0043), delayed recall (51% vs. 20%, p = 0.0009), and verbal fluency (19% vs. 2%, p = 0.0098). After WBRT + SRS there was more deterioration in overall QOL (p = 0.001) and functional well-being (p = 0.006) at 3months. Intracranial tumor control at 3 and 6 months were 75.3% and 64.7% with SRS alone vs. 93.7% and 88.4% with SRS + WBRT (p < 0.0001). Median OS was 10.4 for SRS alone vs. 7.4 months for SRS + WBRT respectively (HR = 1.02, p = 0.92). CONCLUSIONS: Decline in QOL and cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS.
TL;DR: Use of barbed progressive tension sutures for abdominal closure after DIEP flap harvest can obviate the need for abdominal drains, reduce postoperative pain and encourage early discharge from the hospital without an increased risk in complications.
Abstract: Summary Background The use of progressive tension sutures alone has been shown to be comparable to using abdominal drains in aesthetic abdominoplasty. This study reviews outcomes with the use of barbed progressive tension suture technique without drains in DIEP donor site closure compared to standard closure with drains. Methods A two year retrospective review was conducted of DIEP flap reconstructions in the enhanced recovery program at Mayo Clinic, Rochester (USA). Donor site closure was divided into barbed progressive tension sutures (B-PTS) without drains, and standard abdominal closure with drains(S-AD). Demographics, perioperative data and donor site complications were documented. Results 93 patients were included in the study, 42 in the B-PTS no drain group and 51 in the S-AD with drains. 81% of all procedures were bilateral and 39% were immediate. Patients were discharged faster to the ward postoperatively and total hospital admission was reduced in the B-PTS group, 3.7 (SD = 1.4) days versus 4.7 (SD = 2.1) days in the standard group (P = 0 Conclusions Use of barbed progressive tension sutures for abdominal closure after DIEP flap harvest can obviate the need for abdominal drains, reduce postoperative pain and encourage early discharge from the hospital without an increased risk in complications. Level of evidence III.
Harvard University1, Mayo Clinic2, University of Texas MD Anderson Cancer Center3, University of California, Los Angeles4, Memorial Sloan Kettering Cancer Center5, National Institutes of Health6, Princess Margaret Cancer Centre7, Henry Ford Health System8, University of California, San Diego9, University of California, San Francisco10, Johns Hopkins University11
TL;DR: Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013.
Abstract: Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting.
TL;DR: The tenth author’s name is spelled incorrectly and the correct name is: Alvaro Moreno-Aspitia.
Abstract: The tenth author’s name is spelled incorrectly. The correct name is: Alvaro Moreno-Aspitia.
The Academic Editor field is missing from the published paper. The name of the Academic Editor is: Aamir Ahmad, Wayne State University School of Medicine, United States.
TL;DR: It is reported that in exploratory analyses from this subset HER2+ population from N9831, S-TILs were associated with RFS in patients treated with chemotherapy alone, and were not shown to be associated with rfs in patients treating with chemotherapy plus trastuzumab.
Abstract: Background: Tumor-infiltrating lymphocytes (TILs) at diagnosis are reported to be prognostic in triple-negative breast cancer (BC). Analysis of a small subset of 209 HER2+ patients (pts) with 49 events concluded that higher levels of S-TILs are associated with increased trastuzumab benefit (Loi, 2014). Here we report the largest study to date evaluating S-TILs and their prognostic and predictive association with clinical outcome in N9831 pts treated with either chemotherapy or chemotherapy plus trastuzumab. Methods: Samples assessed were from primary tumors of pts on N9831 arm A (standard AC→T chemotherapy) and arm C (concurrent chemotherapy with trastuzumab) (Perez, 2011). S-TILs were evaluated on HE ≥60% S-TILs was used for the categorical cutoff (Denkert, 2010). The association between S-TILs, treatment (tx) and recurrence-free survival (RFS) was studied and the interaction between S-TILs, trastuzumab benefit and RFS was calculated. Results: 489 pts from arm A (chemo) and 456 pts from arm C (chemo with trastuzumab) were assessed and were similar to pts in the overall trial; all had RFS information and a median follow-up of 4.4yr. Tumors from 54% of pts in arms A and C were HR+; 14% were node-negative. Tumors with high S-TILs were more likely to be hormone receptor-negative (p Conclusions: In exploratory analyses from this subset HER2+ population from N9831, S-TILs were associated with RFS in patients treated with chemotherapy alone, and were not shown to be associated with RFS in patients treated with chemotherapy plus trastuzumab. Citation Format: Edith A Perez, Karla V Ballman, S Keith Anderson, E Aubrey Thompson, Sunil S Badve, Helen Bailey, Frederick L Baehner. Stromal tumor-infiltrating lymphocytes(S-TILs): In the alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-06.
TL;DR: Proposed methods to decrease the FNR include clip placement in the positive node at initial diagnosis with confirmation of resection of the clipped node at surgery and inclusion of residual metastatic cells identified by immunohistochemistry (IHC) for cytokeratins and disease measuring.
Abstract: Background: The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial (Alliance) reported a false negative rate (FNR) of 12.6% with sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy in women presenting with node-positive breast cancer. Proposed methods to decrease the FNR include clip placement in the positive node at initial diagnosis with confirmation of resection of the clipped node at surgery and inclusion of residual metastatic cells identified by immunohistochemistry (IHC) for cytokeratins and disease measuring
TL;DR: The dermis has a significant role in enhancing overall DIEP flap perfusion through preservation of indirect linking vessels organized in the subdermal plexus and leads to a decrease in such complications as partial or total flap necrosis, as well as fat necrosis.
Abstract: Summary Background Single-stage breast reconstruction following skin-sparing or nipple-sparing mastectomy with free deep inferior epigastric perforator (DIEP) flap usually does not require a large skin paddle. Most of the flap skin paddle is removed, and the flap is placed under native, conserved skin to provide adequate volume to the reconstructed breast mound. We hypothesized that conservation of intact dermis and its subdermal plexus has a critical role in overall flap perfusion through recruitment of indirect linking vessels. The study goal was to investigate and compare the vascularity of DIEP flaps with intact dermis versus DIEP flaps with the dermis removed. Methods Twelve hemi-DIEP flaps were harvested from fresh cadavers. The largest dominant perforator was cannulated using a 24-gauge butterfly catheter. Flaps were imaged with computed tomography (CT) after injection of a contrast agent. After scanning, the contrast agent was flushed out of the flap. The flap skin was removed with cautery at the subdermal dissection plane. The flaps were reimaged with CT after injection of the contrast agent. Three-dimensional (3-D) CT angiographic reconstructions were obtained for each protocol stage, and the percentage of flap perfusion was calculated. Flap vascularity with and without dermis was compared. Results A mean difference of 25.9% in flap perfusion occurred when the dermis was removed ( P Conclusion The dermis has a significant role in enhancing overall DIEP flap perfusion through preservation of indirect linking vessels organized in the subdermal plexus. Despite being time consuming, a cautious de-epithelialization of the DIEP flap should be performed to retain dermis integrity. Enhancement of flap vascularity ultimately leads to a decrease in such complications as partial or total flap necrosis, as well as fat necrosis.
TL;DR: A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors, and trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays.
Abstract: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. N9831 tested the addition of trastuzumab to chemotherapy in stage I–III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative 10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. Clinicaltrials.gov NCT00005970
. Registered 5 July 2000.
TL;DR: In this preliminary analysis, patients receiving TMZ alone experienced shorter PFS and time to death from tumor progression, compared to those receiving RT alone or RT + TMZ.
Abstract: BACKGROUND: CODEL originally included an RT-alone control arm. Following EORTC 26951/RTOG 9402 reports, the original study closed for revision of the control arm to RT + adjuvant PCV. We performed an analysis of pts randomized per the original CODEL design. METHODS: Adults (>18 yr) with newly diagnosed, 1p/19q codeleted WHO grade III anaplastic glioma were randomized to RT (5940 cGy) (Arm A); vs. RT + TMZ (75mg/M2/D +RT; 150-200mg/M2, D1-5 q28D X 6-12 (Arm B); vs. TMZ (150-200 mg/M2, D1-5q28D X 12 (Arm C). Stratification included Age ( 50); Group [North America vs EORTC]; and ECOG status (0-1 vs. 2). Primary endpoint was overall survival. PFS was compared by logrank test (Arm C vs. Arms A + B (pooled). RESULTS: 36 pts (N.A.-53%, EORTC-47%) were randomized (Arm A-12; Arm B-12; Arm C-12), with balance for age, ECOG status, and extent of resection. Grade 3+ toxicity occurred in 25%, 41% and 31% (Arms A, B and C, respectively). No pts withdrew or died from toxicity. All treatment cycles were completed in 92%, 83% and 58% (Arms A, B and C, respectively). Progression during treatment occurred in 5/12 (42%) TMZ alone pts, vs. 0/24 (0%) on RT arms. With median follow-up of 3.4 yrs, 6/12(50%) of the TMZ alone pts have progressed, vs. 2/24(8%) on RT Arms (p = 0.002); death from disease progression occurred in 5%(3/12) TMZ alone pts vs. 4% (1/24) on RT Arms (A-0; B-1). Median PFS was 2.5 yr for TMZ alone vs. not reached for pts on RT Arms. CONCLUSIONS: In this preliminary analysis, patients receiving TMZ alone experienced shorter PFS and time to death from tumor progression, compared to those receiving RT alone or RT + TMZ. Accordingly, the Alliance DSMC recommended closure of Arm C. CODEL has been revised to a two-arm comparison of RT + adjuvant PCV vs. RT + concomitant/adjuvant TMZ. (Support: U10CA180821)
TL;DR: Screening UA and UCx at admission for elderly trauma patients identifies these UTIs and is cost-effective; up to $16,144 savings was realized.
Abstract: Introduction
Catheter-associated urinary tract infections (CAUTI) have been deemed “reasonably preventable” by the Centers for Medicare and Medicaid (CMS) thereby eliminating reimbursement. Elderly trauma patients, however, are at high risk for developing urinary tract infections (UTI) given their extensive comorbidities, immobilization, and environmental changes in the urine which provide the ideal environment for bacterial overgrowth. Whether these patients develop CAUTI as a complication of their hospitalization or have asymptomatic bacteriuria (ASB) or UTI upon admission must be determined in order to justify the “reasonably preventable” classification. We hypothesize that a significant proportion of elderly patients will present with ASB or UTI on admission.
TL;DR: Age alone should not be a contraindication to SLNB and CLND for melanoma patients with high sensitivity and a low false negative rate, and SLN status was independently associated with melanoma-specific survival.
Abstract: Background Among older melanoma patients, lymphatic mapping failure, lower rates of SLN positivity and poor prognosis are reported reasons for omission of sentinel lymph node biopsy (SLNB). We investigated reasons for non-compliance with guidelines, sensitivity and prognostic significance of SLNB and completion lymphadenectomy (CLND) for elderly melanoma patients. Methods Retrospective review of patients ≥65 years with ≥1 mm thick melanoma treated at a single Institution. Wilcoxon, chi-square and Fisher's exact tests were used for analysis as appropriate. Univariable and multivariable Cox regressions were used to analyze time-to-event variables. Results 72 of 358 patients (20%) did not undergo SLNB. Reasons for omission included selective neck dissection in 26 (7%), patient refusal in 11 (3%), physician recommendation in 15 (4%) and significant comorbidities in 8 (2%). Of the 286 patients undergoing SLNB, only 5 (1.7%) had lymphatic mapping failures. 76 patients (26.6%) were SLN-positive. The sensitivity of SLNB was 90.5%, the negative predictive value was 96.3% and the false negative rate was 3.8%. Sixty-seven (88%) SLN-positive patients underwent CLND and 10 (15%) had positive non-SLNs. Reasons for omission of CLND included patient refusal in 3 (4%), surgeon recommendation in 5 (7%) and postoperative complication in 1 (1%). SLN and non-SLN status were independently associated with disease-free survival. SLN status was independently associated with melanoma-specific survival. Conclusions SLNB was successful in 98.7% of elderly patients with high sensitivity and a low false negative rate. Only 2% of our elderly patients appeared too frail for SLNB. Age alone should not be a contraindication to SLNB and CLND for melanoma.
TL;DR: No differences in pCR rates were observed according to race, age or BMI after accounting for tumor characteristics, and similar associations were observed when stratified by subtype.
Abstract: 33 Background: Pathologic complete response (pCR) is an important prognostic indicator and surrogate endpoint, particularly for patients with hormone receptor-negative breast cancer. Previous studies have suggested differential response to pre-operative therapy by age and body mass index (BMI), though no association has been seen by race. We assessed associations of age at diagnosis, BMI and race with pCR accounting for breast cancer subtype. Methods: Women enrolled in four clinical trials of neoadjuvant chemotherapy (CALGB 40601 and 40603; ACOSOG Z1031 and Z1041) were eligible for this analysis. Age, race, and BMI were abstracted from patient records at baseline. Tumor subtype was assessed using immunohistochemical staining and/or fluorescence in situ hybridization. Logistic regression models were used to determine the association of race/ethnicity and age at diagnosis with pCR, the absence of residual invasive disease in the breast after neoadjuvant chemotherapy, adjusting for subtype (HER2+, ER+/ HER2-...
TL;DR: An overview of the role of biomarkers in brain tumor trials is presented in the context of existing clinical trials as well as trials that may be launched within the next several years.
Abstract: Treatment of brain tumors is increasingly informed by biomarkers. One use is to appropriately group tumors with similar genetic/genomic characteristics and to design trials separately for the individual groups. The biomarker's use is to predict patient response so that the most effective treatment can be selected for patients based on their tumor characteristics. Trial designs that recruit unselected patients are poorly suited for identifying treatments effective only in subsets of patients given the relatively small numbers of patients available for trials. Investigators are beginning to use different designs that better account for tumor heterogeneity. In this article, an overview of the role of biomarkers in brain tumor trials is presented in the context of existing clinical trials as well as trials that may be launched within the next several years.
TL;DR: This study investigates whether combination therapy induced immune responses to other tumor antigens and whether immune responses are associated with survival among patients with HER2-positive breast cancer.
Abstract: 587 Background: The addition of trastuzumab to chemotherapy improves response to therapy and extends survival among patients with HER2-positive (HER2+) breast cancer. Prior work showed that trastuz...
TL;DR: The letter by Gavin et al raises two separate issues regarding the authors' article on predicting benefit from trastuzumab in the adjuvant treatment of a breast cancer cohort and the most important aspect of the published work goes beyond the genomic signature itself and includes the observation that one may be able to build reliable predictive models using a biologic process approach.
Abstract: The letter by Gavin et al raises two separate issues regarding our article on predicting benefit from trastuzumab in the adjuvant treatment of a breast cancer cohort. The first, and most important, of these issues is summarized in the last paragraph of the letter and relates to the level of validation that is required for a clinically meaningful genomic signature. We believe that it is generally understood that three levels of validation are required: analytic validation, which involves development of a stable assay with well-defined cut points and genomic components; clinical validation, which requires an independent sample cohort; and clinical utility. Our understanding of these processes, insofar as we can determine, is no different from that expressed by Gavin et al. It seems obvious that a predictive model, developed using microarray data, is likely to require qualitative adjustment, quantitative refinement, and strict analytic validation when translated to a different platform. It is equally obvious that no signature can advance to the clinic without rigorous validation. Regarding these points, we are in complete agreement with Gavin et al. The second point that Gavin et al raise relates to the assertion that any 15 genes, chosen at random, can be used to build a model that is predictive of therapeutic response within a given cohort of samples. These would be surprising results. We are unable to evaluate this claim without access to the methods and data used to produce these results. However, we have built models on the basis of genes with significant adjusted Cox hazard ratios, determined from microarray analysis of N9831 samples. Our experience indicates that, to the extent that models built using such genes survive Monte Carlo cross validation, they tend to be prognostic, rather than predictive. Conversely, the model that we have published was built using genes with significant interaction terms; this model proved to be stable to Monte Carlo cross validation and to be predictive, rather than prognostic. Thus, our analyses would not seem to be consistent with the claim that predictive models can be built using any randomly selected set of genes. Be that as it may be, we emphatically agree that the predictive model that we have published will require rigorous analytic validation and will likely require both qualitative and quantitative adjustment when transferred to the NanoString (NanoString Technologies, Seattle, WA; or another) platform. We would like to emphasize that the most important aspect of our published work goes beyond the genomic signature itself and includes the observation that one may be able to build reliable predictive models using a biologic process approach, which, in our case, identifies immune function genes as important components of therapeutic response. This approach is analogous to that taken by Pogue-Geile et al, who have modeled trastuzumab benefit on the basis of a signature that reads out ESR1 (estrogen receptor) and ERBB2 (erb-b2 receptor kinase 2) expression and activity. The model that will ultimately emerge from our analytic validation studies will be developed on the concept that one can also model benefit on the basis of immune function genes, as demonstrated using the DASL (cDNA-Mediated, Annealing, Extension, and Ligation) platform. The value of the microarray data is that they define a process that can be interrogated in a quantitative manner in reference to potential benefit. The fully mature immune function gene expression model will clearly need to be validated in an independent data set, and we have been working with Paik et al (personal communication, March 2014) and the National Cancer Institute to obtain RNA from samples collected from the National Surgical Adjuvant Breast and Bowel Project B-31 trial to this end. We are cognizant of the fact that such samples are precious and irreplaceable, and that application of our model to such samples will require refinement of the model after transferring it to the NanoString platform and locking down all qualitative and quantitative parameters. We are currently working with statisticians at the National Cancer Institute, who will review the code, the data used to develop the model, and the thresholds used to define immune function gene enrichment. It is our expectation that this process will be completed in the next few months, at which time we will report the results of the validation. Moreover, the signature, the code, and the data will be made publicly available. Again, it is our understanding that our approach is in agreement with the generally accepted precepts of analytic and clinical validation of genomic models for clinical prediction, along the lines of those described by Gavin et al as essential steps in the process of signature development and validation.
TL;DR: LCP at BL was associated with lower QoL, worse physical symptoms, AEs and function mid-therapy, but not mental health, and this information may be useful for oncology professionals to counsel older ESBC pts with LCP receiving adjuvant chemo.
Abstract: Background: In CALGB-49907 (NEJM 2009;360:2055), older patients (pts) with ESBC were randomized to standard adjuvant chemo (AC or CMF versus capecitabine). The objective of this secondary QoL analysis is to assess if pts’ BL chemo preference (CP, defined as high or low), is associated with the following during and after completion of chemo: self and professional-reported toxicity, changes in mental health, function, QoL, recurrence-free (RFS) and overall (OS) survival. Patients and Methods: Of 633 trial pts 350 participated in the QoL substudy; 145/350 pts completed the BL assessment regarding CP. CP was measured by asking the amount of benefit women would require to choose adjuvant chemo in a hypothetical situation, irrespective of chemo agents. Women who chose chemo for an increase in OS of ≤12 months (mo) were designated as high chemo preference (HCP) and those who chose >12 mo were designated low chemo preference (LCP). CP associations were evaluated with: BL perception of self-health and perceived QoL on chemo; patient reported outcomes (PROs), changes in function and QoL (based on EORTC-QLQ-C30); anxiety and depression (Hospital Anxiety and Depression Scale); observed grade 3-5 adverse events (AEs) by NCI common toxicity criteria (CTC v2.0). Pts were assessed at midtreatment and at 1, 12, 18 and 24 mo post-treatment. Chi-square tests, t-tests, and Cox models were used for categorical, continuous, and time-to-event variables, respectively. Results: The demographic and tumor characteristics of women (median age 71) who provided CP at BL were not different from women in the QoL subset or from non-QoL pts. 68/145 (47%) women had a HCP. CP groups did not differ based on age, surgery type, tumor and nodal stage, hormone receptor status, performance status, chemo assignment, education, marital or employment status except the LCP group had a higher proportion of white women (95% vs. 78%, p=0.004). At BL, there were no differences in perception of self-health based on CP but women with LCP predicted QoL on chemo to be worse than women with HCP (p=0.006) and reported greater nausea/vomiting. Mid-treatment, LCP pts reported worse nausea/vomiting, financial worries, and cancer symptoms. Post-treatment, LCP pts had worse constipation (at 1 mo) and financial worries (at 24 mo). There were no differences based on CP for dyspnea, pain, fatigue, insomnia, anxiety or depression at any timepoint. Mid-treatment, LCP women reported lower QoL and worse social, emotional and physical function compared to HCP women. These scores were not significantly different after treatment completion. LCP women had significantly higher rates of grade 3-5 AEs (53 vs. 34%, p=0.02) during treatment but these did not persist post-therapy. CP was not significantly associated with OS (HR =0.75, p=0.36) or RFS (HR=0.94, p=0.84). Conclusions: LCP at BL was associated with lower QoL, worse physical symptoms, AEs and function mid-therapy, but not mental health. Mid-therapy declines in women with LCP largely reversed post-therapy. This information may be useful for oncology professionals to counsel older ESBC pts with LCP receiving adjuvant chemo. Citation Format: Ajeet Gajra, Linda McCall, Hyman B Muss, Harvey J Cohen, Aminah Jatoi, Karla V Ballman, Ann H Partridge, Linda Sutton, Barbara A Parker, Gustav Magrinat, Jaqueline M Lafky, Arti Hurria. Association of patient preference for adjuvant chemotherapy (chemo) at baseline (BL) with toxicity, mental health, function, quality of life (QoL) and survival in older women with early stage breast cancer (ESBC) [CALGB 49907 Alliance] [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-07.
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20 Apr 2015TL;DR: This article provided methods and materials involved in identifying mammals having breast cancer (e.g., HER2-positive breast cancer) responsive to trastuzumab as well as methods involved in treating mammals having cancer responsive to the drug.
Abstract: This document provides methods and materials involved in identifying mammals having breast cancer (e.g., HER2-positive breast cancer) responsive to trastuzumab as well as methods and materials involved in treating mammals having breast cancer (e.g., HER2-positive breast cancer) responsive to trastuzumab. For example, methods and materials for using expression level profiles to identify mammal having HER2-positive breast cancer with an increased likelihood of being responsive to trastuzumab are provided.