tbuckley/cabot-search huggingface dataset:
Bortezomib appears to overcome poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials
Authors: S. Jagannath, P. G. Richardson, P. Sonneveld, D. Irwin, M. W. Schuster, E. A. Stadtmauer, T. Facon, J. L. Harousseau, J. M. Cowan, K. C. Anderson
Journal: Journal of Clinical Oncology (2005)

6501 Background: Deletion of chromosome 13 [del(13)] by conventional cytogenetics is an important adverse prognostic factor for survival in multiple myeloma (MM) patients (pts) regardless of treatment (conventional chemotherapy and autologous or mini-allogeneic transplantation). However, in a phase 2 trial with bortezomib (VELCADE) (SUMMIT), del(13) did not adversely affect survival or response rate (RR). Therefore, we wanted to support this observation in the recently concluded large phase 3 trial, APEX, which allowed us the opportunity to evaluate the prognostic value of del(13) in both the conventional treatment arm (dexamethasone, dex) and the bortezomib arm. Methods: The APEX trial was a randomized multi-center international phase 3 trial comparing bortezomib and high-dose dex in 669 pts with relapsed MM. This study demonstrated improved survival of pts on bortezomib vs those on dex. Metaphase cytogenetics (MCG) in 168 evaluable pts showed del(13) in 24 (14%). A match-paired analysis of 21 of the 24 evaluable del(13) pts with 41 pts with wild type chromosome 13 balanced for adverse prognostic factors (treatment, age, lines of prior therapy, β2M, and albumin) was performed to analyze the impact of del(13) on survival. Results: A significant decrease in survival was found in 21 evaluable pts with del(13) compared with 41 pts without this deletion [HR (95% CI) = 3.24 (1.27, 8.23), P = 0.0090]. Detection of del(13) was associated with markedly decreased survival in the dex arm [HR (95% CI) = 5.72 (1.65, 19.81), P = 0.0020]. In contrast, in the bortezomib arm, del(13) was not associated with a difference in survival [HR (95% CI) = 1.23 (0.26, 5.74), P = NS] or RR [25% del(13) vs 35%, P = NS]. Conclusions: Bortezomib therapy appears to overcome the adverse impact of del(13) on survival or response rate consistent with findings in SUMMIT. Del(13) by metaphase cytogenetics appears to remain an adverse prognostic factor for survival in the dex arm. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Millennium, Ortho-Biotech, Pharmion Amgen, Celgene, Millennium, Ortho-Biotech, Roche Millennium
STAT3 as a potential molecular target to sensitize colorectal cancer cells to chemoradiotherapy.
Authors: Marian Grade
Journal: Journal of Clinical Oncology (2013)

434 Background: Resistance to preoperative chemoradiotherapy represents a major clinical problem in the treatment of patients with locally advanced rectal cancer. Therefore, the identification of molecular biomarkers that differentiate responsive and resistant tumors is exceedingly important, because this may lead to the identification of novel molecular targets whose modification could be harnessed to sensitize a priori resistant tumors to multimodal treatment. Methods: We recently established an in vitro model for 5-FU based chemoradiotherapy, and correlated differences in treatment sensitivity of 12 colorectal cancer cell lines with pretherapeutic gene expression profiles. One gene the expression of which correlated positively with treatment resistance was the signal transducer and activator of transcription 3, STAT3. To test the functional relevance of this observation, we first determined STAT3 mRNA and protein expression levels in all cell lines. Next, we established doxycycline-inducible stable shRNA single-cell clone (SCC) populations. Successful silencing of STAT3 was detected by Western blot analysis. The induced SCCs were treated with 3 µM 5-FU, and subsequently exposed to 0, 1, 2, 4, 6, and 8 Gy of X-rays. In addition, STAT3 was inhibited using two different siRNAs, and a small-molecular inhibitor (STATTIC). Results: STAT3 was significantly overexpressed in resistant cells. In SW480 and SW837 cells, both shRNA- and siRNA-mediated silencing as well as STATTIC-induced inhibition of STAT3-phosphorylation resulted in a significantly increased chemoradiosensitivity, with dose-reduction factors of 1.8 to 2. Conclusions: These results highlight the potential relevance of STAT3 as a novel molecular target to sensitize a priori resistant tumor cells to chemoradiotherapy.
IO-125: A novel supramolecular platinum chemotherapy for triple negative breast cancer.
Authors: Aniruddha Sengupta, Sanghamitra Mylavarapu, Smita Kumari, Samad Hossain, Heeralal B, Nimish Gupta, Arindam Sarkar, Aasif Ansari, Thirumurthy Velpandian, Monideepa Roy, Shiladitya Sengupta
Journal: Journal of Clinical Oncology (2015)

153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. Methods: Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. Results: We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cation transporters known for transporting current platinum chemotherapies, IO-125 is also internalized via caveolin-mediated endocytic pathway, resulting in 10-20 fold greater uptake into cells as compared to oxaliplatin. Studies have implicated caveolin in TNBC progression and drug resistance, and harnessing this mechanism could confer enhanced activity. In animals bearing MDA-MB-231 xenografts, three cycles of IO-125 at well-tolerated doses (35 mg Pt/kg) resulted in significant tumor growth inhibition as compared to reported tumor inhibitions seen with existing platinum chemotherapies. Pharmacokinetic studies conducted in mice and rabbits indicate markedly improved profile of IO-125 as compared to oxaliplatin, showing a significantly higher area-under-the-curve (AUC), a substantial reduction in clearance and volume of distribution, with an enhanced half-life. Conclusions: Collectively, our findings demonstrate that IO-125 exhibits superior pharmacokinetics profile and biodistribution to tumors, resulting in enhanced anti-tumor activity in a TNBC xenograft model. Based on these observations, we propose that IO-125 may emerge as a potentially effective platinum-based drug for TNBC patients.
BRCA+ test result impact and timing on surgical treatment decisions for patients with breast cancer.
Authors: K. M. Doll, C. B. Weldon, J. R. Trosman, H. H. Wetzel, T. J. Fallen, W. J. Gradishar, J. C. Schink
Journal: Journal of Clinical Oncology (2011)

626 Background: In a study of insurance claims data we found BRCA mutation analysis performed before breast cancer surgery affected surgical approach (Trosman JR, ASCO-Abstract-666-2010). Patients with BRCA mutation have a higher risk of breast cancer recurrence. These patients are more likely to view mastectomy as the best way to reduce future BC recurrence while avoiding multiple surgeries and radiation (Schwartz, JCO-2004). The goal of this study is evaluation of BRCA test result impact on BC surgical decisions. Methods: This is a retrospective review of medical records and insurance claims for 302 breast cancer patients who underwent BRCA testing and definitive surgery between 07/01/2006 and 09/30/2010. Following an IRB approved protocol; we used simple frequencies and Fisher's exact test to evaluate occurrences of BRCA test results relative to surgical timing and decisions. Results: The BRCA test was performed pre-surgery in 37% (112/302) of this cohort. The majority of women, 71% (79/112), tested pre-surgery had a mastectomy compared to 38% (73/190) of women tested after surgery (p=.0001). Of women with BRCA positive results, 83% (19/23) tested pre-surgery had a mastectomy compared to 44% (17/39) of women tested after surgery (p=.0003). There was a significant trend toward bi-lateral mastectomy in the pre-surgery BRCA+ woman (13/23) as compared to (7/39) of the BRCA+ women tested after surgery (p=.004). Of women with known negative BRCA results, 70% (39/56) tested pre-surgery had a mastectomy compared to 36% (34/94) of women tested after surgery (p=.0001). Conclusions: Most women with positive BRCA test results prior to surgery chose mastectomy, a majority had double mastectomies. Less than half of women with positive BRCA results after surgery chose mastectomies. Conducting BRCA mutation analysis prior to breast cancer surgery is associated with a more radical surgical approach. Interestingly, women with known negative BRCA results were more likely to choose mastectomies than women without BRCA test results. Further research is needed to investigate how known factors such as BRCA results, experience of genetic counseling, and awareness of risks based on family history impact surgical decisions.
Cellular function of the mononuclear phagocyte system (MPS) as a phenotypic probe for pegylated liposomal doxorubicin (PLD) pharmacokinetics (PK) in patients with recurrent ovarian cancer.
Authors: W. P. Caron, J. C. Lay, A. M. Fong, N. M. La-Beck, S. E. Newman, D. L. Clarke-Pearson, W. R. Brewster, L. Van Le, V. L. Bae-Jump, P. A. Gehrig, W. Zamboni
Journal: Journal of Clinical Oncology (2011)

2550 Background: A phenotypic probe is a test that can be administered to a patient as a potential indicator of a drug’s PK which can then be used to individualize therapy. PK of nanoparticle agents, such as pegylated liposomes are dependent upon the carrier and not the encapsulated drug. Since nanoparticles are cleared via the MPS, including blood monocytes (MO), we hypothesized that circulating MO could potentially play a major role in nanoparticle clearance (CL) and that the ability to measure MO functional activity in blood samples can be used to predict CL in patients. Methods: PLD 40mg/m2 IV x 1 was administered to patients (n=6) with recurrent ovarian cancer. PK samples were obtained at time 0, 24, 48, 72, 96, 168 h and day 28 post dose. Plasma was processed to measure encapsulated and released doxorubicin using solid phase separation and HPLC. Data was analyzed with WinNonlin to obtain PK parameters. MO phagocytic function (uptake of FITC-labeled opsonized E. Coli) and oxidative burst activity (intracellular oxidation of dihydrorhodamine 123) were assessed via flow cytometry at time 0 h, 48 h, 96 h, and on day 28. For both assays, changes in mean fluorescent intensity of the gated MO population, following incubation of whole blood with the appropriate substrate, served as an index of activity. Results: There was a direct linear relationship between PLD CL and both phagocytosis (R2 = 0.87) and oxidative burst activity (R2 = 0.64) in blood MO. After beginning PLD, the phagocytic capacity of MO declined slightly but returned to baseline prior to the start of cycle 2, whereas oxidative burst activity increased and remained elevated. Mean ± SD ratios of MO phagocytosis at 48 h, 96 h and day 28 to pre-PLD were 0.87 ± 0.23, 0.73 ± 0.45, and 1.01 ± 0.70, respectively. Mean ± SD ratios of MO oxidative burst at 48 h, 96 h and day 28 to pre-PLD were 1.54 ± 1.9, 1.16 ± 0.86, and 2.01 ± 0.95. Conclusions: These findings indicate that probes of MPS function predict PLD CL and thus may be useful for individualizing PLD therapy in ovarian cancer and other malignancies. Changes in phagocytosis and oxidative burst need to be further evaluated during cycle 1 and subsequent cycles.
Clinical and biologic features of ER- PR- HER-2- breast cancer compared to estrogen or HER-2 driven phenotypes
Authors: G. Arpino, H. Weiss, R. Elledge
Journal: Journal of Clinical Oncology (2005)

9607 Background: Estrogen receptor (ER)- progetserone receptor (PR)- HER-2- breast cancer may define a distinct biologic subtype of disease with a more aggressive behavior. Methods: To explore this hypothesis, the clinical characteristics, biologic features, disease free survival (DFS) and overall survival (OS) were compared in ER- PR- HER-2- (triple negative = TN), ER+ PR+ HER-2- (estrogen driven = ED) and ER- PR- HER-2+ (HER-2 driven = HD) tumors. Of 2,450 patients in the database in which ER, PR and HER-2 were all known, 1,460 had one of the above three phenotypes. Results: 11.2% of all tumors were TN. Compared to HD tumors, TN tumors were modestly smaller in size, p=.04, had less nodal involvement, p=.0009, but had similar rates of high proliferation, 72.5% vs. 80.5%, with high/intermediate S-phase fraction, p=.21, aneuploidy, 63.1% vs. 54.4%, p=.51 and EGFR expression measured by radioligand binding assay, 46.3% vs. 46.4%, p=.92. Compared to ED tumors, TN did not significantly differ in tumor size, p=.17 and nodal status, p=.73. Proliferation, however, was much higher for TN vs. ED, 72% vs. 37%, high/intermediate S-phase fraction, p<.0001, as well as aneuploidy, 63.1% vs. 43.8%, p<0001. EGFR expression was 6.5 times higher in TN than ED, 46.3% vs. 7.3%, p<.0001. DFS and OS did not differ significantly for systemically untreated TN compared to ED patients. Conclusions: EGFR expression is similarly high in both TN and HD breast cancer, approximately 40–50%. TN tumors proliferate much more rapidly, have high genomic instability and EGFR expression compared ED phenotype, but have similar metastatic potential. No significant financial relationships to disclose.
Recurrence rates for ductal carcinoma in situ: Analysis of 2,996 patients treated with breast-conserving surgery over 30 years.
Authors: Kimberly J. Van Zee, Preeti Subhedar, Cristina Olcese, Sujata Patil, Monica Morrow
Journal: Journal of Clinical Oncology (2015)

32 Background: Randomized trials of radiation after breast-conserving surgery (BCS) for DCIS found substantial rates of recurrence, with half of recurrences invasive. Decreasing local recurrence rates for invasive breast carcinoma have been observed, and are largely attributed to systemic therapy improvements. Here we examine recurrence rates after BCS for DCIS over 3 decades at one institution. Methods: We retrospectively reviewed a prospectively maintained database of DCIS patients undergoing BCS from 1978–2010. Cox proportional hazard models were used to investigate the association between treatment period and recurrence, controlling for other variables. Results: 363 (12%) recurrences among 2996 cases were observed. Median follow-up for patients without recurrence was 75 months (range 0–30 years); 732 were followed for ≥ 10 years. The 5-year recurrence rate for 1978–1998 was 13.6% versus 6.6% for 1999–2010 (hazard ratio [HR] 0.62, p &lt; 0.0001). After controlling for age, family history, presentation (radiologic vs clinical), nuclear grade (non-high vs. high grade), necrosis, number of excisions ( ≤ 2 vs ≥ 3), margin status (positive/close vs negative), radiation, and endocrine therapy, treatment period remained significantly associated with recurrence, with later years associated with a lower HR (0.74, p = 0.02) compared to earlier. After stratification by radiation use, and adjustment for 7 other factors, the decrease in recurrence rates was limited to those without radiation (HR 0.62, p = 0.003); there was no decline in recurrence rates among those receiving radiation (HR 1.13, p = 0.6). Conclusions: Recurrence rates for DCIS have fallen over time. Increases in screen-detection, negative margins, and use of adjuvant therapies only partially explain the decrease. The unexplained decline is limited to women not receiving radiation, suggesting it is not due to changes in radiation efficacy, but may be due to improvements in radiologic detection and pathologic assessment. The lower recurrence risk observed for DCIS patients treated in more recent years is important for patient education, especially in view of the widely reported recent increase in use of mastectomy.
Impact of perivesical lymph nodes on survival after radical cystectomy.
Authors: Brian Robin Hu, Raj Satkunasivam, Jie Cai, Gus Miranda, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2014)

350 Background: Lymph node staging for bladder cancer is dependent upon both location and number. This study characterizes perivesical (PV) lymph nodes (LN) found at radical cystectomy and evaluates their prognostic impact. Methods: We reviewed our Institutional Review Board-approved database from 1971-2009 including all patients who underwent radical cystectomy with pelvic lymphadenectomy for curative intent for urothelial carcinoma. Clinical and pathologic data were obtained. Patients were analyzed in three groups: PV LN+/other LN-, PV LN+/other LN+, and PV LN-/other LN+. Kaplan-Meier curves were used to estimate recurrence free survival (RFS) and overall survival (OS). Multivariable Cox regression (including pathologic T stage, number of positive LN, highest level of positive LN, chemotherapy, and margin status) was performed to evaluate associations between PV LN status and survival. Results: A total of 2,045 patients underwent radical cystectomy for urothelial carcinoma of which 2011 met inclusion criteria. PV LN were identified in 936 (47%) patients, positive in 197 (10%) patients, and represented isolated LN positive disease in 101 (5%) patients. On univariate analysis, positive PV LN were associated with a higher likelihood of extravesical disease (&gt;pT2) when compared with other positive LN (p=0.023). There was no significant difference in RFS or OS when comparing patients with negative PV LN to those with PV LN not identified. On multivariable analysis, patients with PV LN+/other LN+ had a significantly worse RFS (HR 1.75, 95% CI 1.29-2.38, p&lt;0.001) and OS (HR 1.66, 95% CI 1.27-2.19, p&lt;0.001) when compared with PV LN-/other LN+. There was no significant difference in RFS or OS when comparing patients with PV LN+/other LN- to PV LN-/other LN+. Conclusions: PV LN are identified in a significant portion of patients after radical cystectomy with pelvic lymphadenectomy. Positive PV LN, when in combination with other positive LN, portends worse survival even when correcting for the number of positive LN. No significant difference in survival was seen comparing patients with isolated positive PV LN to those with other positive LN. This study highlights the importance of PV LN in pathologic analysis and bladder cancer staging.
Hodgkin lymphoma of the elderly veterans: Veterans Affairs Cancer Registry analysis.
Authors: J. Krishnamurthy, T. Tashi, W. Gonsalves, R. Thota, P. T. Silberstein, S. Subbiah
Journal: Journal of Clinical Oncology (2011)

9138 Background: Hodgkin lymphoma (HL) is a very treatable disease that is known to have a bimodal age distribution. Unlike the younger patients,elderly patients with HL have a prognosis which is still unsatisfactory. Prospective studies selected for elderly patients are rare and randomized trials are missing. We studied the clinical and pathological characteristics, treatment received and survival outcomes of patients ≥60yrs and <60 yrs using the Veterans Affair Cancer Registry database. Methods: Retrospective analysis of 947 patients diagnosed with Hodgkin disease from 1995-2003 was obtained.Demographics, histology, tobacco use, agent orange exposure, stage at presentation, presence of B symptoms and type of treatment received data was extracted.Variables were analyzed with Kaplan-Meier and Cox models. Results: Of the 947 patients 38.8% were >60yrs and 61.2% were <60. Racial distribution among the elderly and the younger HL patients were similiar. In histological subtypes there was an increased prevelance of lymphocyte depleted and nodular lymphocyte predominant subtypes among older patients. Older patients also had higher incidence of stage IV disease compared to their younger counterparts. Overall survival was significantly higher in the <60 years age group (17.83 mos vs 3.23mos). Median survival was better in the <60 years age group when compared for stage at presentation, type of histology, treatment received and absence of B symptoms (P <0.0001) .Multivariate analysis revealed Stage 1(HR=0.68; 0.48-0.95; p=0.024), age <60 years (HR=0.31; 0.26-0.38; p<0.0001) was associated with improved outcomes whereas Lymphocyte depleted (HR=1.44; 1.07-1.93; p=0.015) subtype correlated with poor outcome. Conclusions: HL of the elderly has a dismal prognosis compared to the younger patients.Older age, lymphocyte depleted subtype and advanced stage at presentation are negative prognostic factors in HL patients.Co-morbid illnesses, delay in diagnosis,incomplete staging, inadequate adherence to treatment protocols and failure to maintain dose intensity are other potential factors which needs to be investigated in multi-centre randomized controlled trials.
Clinico-experimental correlations of triptorelin (TPR) based adjuvant treatment in premenopausal breast cancer patients (PBCP)
Authors: R. Bollina, C. Cozzi, G. Beretta, A. Corsini
Journal: Journal of Clinical Oncology (2008)

11507 Background: Consenting female PBCP submitted to quadrantectomy + radiotherapy followed by hormonal manipulation (HT) were treated with parenteral i.m. TPR depot-formulation. Methods: In the case of mixed chemotherapy (CT) +HT adjuvant program, TPR-HT was started after a wash out period from CT of ≥ 6–8 weeks from the last CT dose: HT was preceeded by a complete clinico-lab & imaging evaluation, in order to exclude residual or progressing neoplasia. Initial HT for 3 months was strictly followed with lab investigations of plasma and serum levels of TPR, 17 ß-estradiol (E2) and CBC + routine biochemicals. Chromatographic seranalysis defined TPR levels with the original method developed in our research laboratory (ICACT 2007; XVIII: 329): quantification was obtained with a calibration curve prepared from control sera spiked with increasing amounts of commercially available TPR for clinical daily use. Results: Preliminary results of 10 pts and 98 determinations, including pretreatment controls and at least ≥ 5 samples for each pt, show: 1) a quick initial appearance and increase of TPR serum levels till a steady state level, that is reached from day 7 of TPR-depot administration: these values remain stable for up 3 months; 2) an immediate spike of increased E2 levels in the initial 3 days after TPR, rapidly declining to clinical irrelevant values persisting through out the whole observation period; 3) a sharp significant correlation period between E2 serum levels and stimulatory/inhibitory effect of pt sera in MCF-7 human cultured cells tested as a hormone-sensitive in vitro model; and finally 4) a complete control of BC with persisting complete disease remission in the initial 6 months of follow-up observation.Data collected so far need a more consistant patient sample, before any suggestion tending to modify the treatment timing of TPR and other HT, specifically in the initial period of medical adjuvant therapy for PBCP. Conclusions: Further studies with the combined treatment of TPR plus tamoxifen or anastrozole - as adjuvant HT given for a prolonged time period (≥ 2 till 5 years) - are planned in order to collect more extensive clinico-pharmacokinetic and correlated experimental data. No significant financial relationships to disclose.